fibrin and Inflammation
fibrin has been researched along with Inflammation* in 345 studies
Reviews
66 review(s) available for fibrin and Inflammation
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Fibrinogen and fibrin: synthesis, structure, and function in health and disease.
Fibrinogen is an extraordinary molecule by any estimation. It is large, structurally intricate, and circulates at high concentrations. Its biological end product, insoluble fibrin(ogen) or fibrin, can assume a diverse array of conformations with the ability to interact with numerous plasma proteins and cells and withstand biochemical and biomechanical disruption to facilitate wound healing. Quantitative and qualitative defects in fibrinogen or fibrin are associated with bleeding, thrombosis, inflammation, and diseases affected by these processes. Numerous studies investigating mechanisms by which fibrin(ogen) and fibrin contribute to health and disease have been published. This review for the 20th-anniversary series in the Journal of Thrombosis and Haemostasis summarizes interesting aspects of fibrin(ogen) biology, biochemistry, biophysics, and physiology and highlights exciting findings published in the past 2 decades. Topics: Fibrin; Fibrinogen; Hemostatics; Humans; Inflammation; Thrombosis | 2023 |
The versatile role of the contact system in cardiovascular disease, inflammation, sepsis and cancer.
The human contact system consists of plasma proteins, which - after contact to foreign surfaces - are bound to them, thereby activating the zymogens of the system into enzymes. This activation mechanism gave the system its name - contact system. It is considered as a procoagulant and proinflammatory response mechanism, as activation finally leads to the generation of fibrin and bradykinin. To date, no physiological processes have been described that are mediated by contact activation. However, contact system factors play a pathophysiological role in numerous diseases, such as cardiovascular diseases, arthritis, colitis, sepsis, and cancer. Contact system factors are therefore an interesting target for new therapeutic options in different clinical conditions. Topics: Animals; Blood Proteins; Bradykinin; Cardiovascular Diseases; Fibrin; Humans; Inflammation; Neoplasms; Sepsis | 2022 |
Placental Vascular and Inflammatory Findings from Pregnancies Diagnosed with Coronavirus Disease 2019: A Systematic Review and Meta-analysis.
We aimed to perform a meta-analysis of the literature concerning histopathologic findings in the placentas of women with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection during pregnancy. Searches for articles in English included PubMed, Web of Science, Google Scholar, and reference lists (up to April 2021). Studies presenting data on placental histopathology according to the Amsterdam Consensus Group criteria in SARS-CoV-2 positive and negative pregnancies were identified. Lesions were categorized into: maternal and fetal vascular malperfusion (MVM and FVM, respectively), acute placental inflammation with maternal and fetal inflammatory response (MIR and FIR, respectively), chronic inflammatory lesions (CILs), and increased perivillous fibrin deposition (PVFD). A total of 15 studies reporting on 19,025 placentas, Topics: COVID-19; Female; Fibrin; Humans; Inflammation; Placenta; Pregnancy; Pregnancy Complications, Infectious; SARS-CoV-2 | 2022 |
Current View on the Molecular Mechanisms Underlying Fibrin(ogen)-Dependent Inflammation.
Topics: Endothelial Cells; Fibrin; Fibrinogen; Humans; Inflammation; Leukocytes; src-Family Kinases | 2022 |
Fibrin structure, viscoelasticity and lysis face the interplay of biorelevant polyions.
In the past 5 decades, heparins have been widely used as anticoagulants in the prevention and treatment of thrombosis. Subsequent development of heparin variants of various size and charge facilitated the discovery of their multiple biological actions and nonanticoagulant benefits. Platelet-derived or microbial polyphosphates, as well as DNA released in the course of neutrophil extracellular trap-formation are additional polyanions, which can modulate the development and stability of thrombi associated with cancer or inflammation. In this review, we focus on the size-dependent and electric charge-dependent modulatory effects of the three polyanions of different chemical structure.. The polycationic histones have been recognized as potential biomarkers and therapeutic targets in several diseases related to inflammation and thrombosis. Since combating histones with activated protein C or heparin could cause unwanted bleeding, the quest for nonanticoagulant histone-neutralizing agents is ongoing. Polyanions may neutralize or exaggerate certain histone-mediated effects depending on their electric charge, size and histone effects under investigation. Several prothrombotic effects of polyphosphates and DNA are also size-dependent.. The efficiency of future therapeutics targeting prothrombotic polyanions or histones is not a simple matter of electric charge, but may rely on a delicate combination of size, charge and chemical composition. Topics: DNA; Fibrin; Heparin; Histones; Humans; Inflammation; Polyphosphates; Thrombosis | 2022 |
The Contribution of the Urokinase Plasminogen Activator and the Urokinase Receptor to Pleural and Parenchymal Lung Injury and Repair: A Narrative Review.
Pleural and parenchymal lung injury have long been characterized by acute inflammation and pathologic tissue reorganization, when severe. Although transitional matrix deposition is a normal part of the injury response, unresolved fibrin deposition can lead to pleural loculation and scarification of affected areas. Within this review, we present a brief discussion of the fibrinolytic pathway, its components, and their contribution to injury progression. We review how local derangements of fibrinolysis, resulting from increased coagulation and reduced plasminogen activator activity, promote extravascular fibrin deposition. Further, we describe how pleural mesothelial cells contribute to lung scarring via the acquisition of a profibrotic phenotype. We also discuss soluble uPAR, a recently identified biomarker of pleural injury, and its diagnostic value in the grading of pleural effusions. Finally, we provide an in-depth discussion on the clinical importance of single-chain urokinase plasminogen activator (uPA) for the treatment of loculated pleural collections. Topics: Acute Disease; Animals; Biomarkers; Blood Coagulation; Epithelium; Fibrin; Fibrinolysis; Humans; Inflammation; Lung; Lung Injury; Pleura; Pleural Effusion; Receptors, Urokinase Plasminogen Activator; Thrombolytic Therapy; Urokinase-Type Plasminogen Activator | 2021 |
Plasminogen: an enigmatic zymogen.
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis. Topics: Animals; Antifibrinolytic Agents; Brain; Conjunctivitis; Enzyme Activation; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity; Infections; Inflammation; Mice; Plasminogen; Radiodermatitis; Receptors, Cell Surface; Skin Diseases, Genetic; Thrombosis; Tranexamic Acid; Wound Healing; Wounds and Injuries | 2021 |
PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis.
PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient's life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF. Topics: Animals; Bleomycin; C-Reactive Protein; Disease Models, Animal; Extracellular Matrix; Fibrin; Hemostasis; Humans; Idiopathic Pulmonary Fibrosis; Immunity, Humoral; Immunity, Innate; Inflammation; Mice; Nerve Tissue Proteins; Plasminogen; Serum Amyloid P-Component; Wound Healing | 2021 |
Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin.
Chronic rhinosinusitis (CRS) is one of the most common chronic diseases worldwide. It is a heterogeneous disease, and geographical or ethnic differences in inflammatory pattern in nasal mucosa are major issues. Tissue eosinophilia in CRS is highly associated with extensive sinus disease, recalcitrance, and a higher nasal polyp (NP) recurrence rate after surgery. The prevalence of eosinophilic CRS (ECRS) is increasing in Asian countries within the last 2 decades, and this trend appears to be occurring across the world. International consensus criteria for ECRS are required for the accurate understanding of disease pathology and precision medicine. In a multicenter large-scale epidemiological survey, the "Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis study," ECRS was definitively defined when the eosinophil count in nasal mucosa is greater than or equal to 70 eosinophils/hpf (magnification, ×400), and this study proposed an algorithm that classifies CRS into 4 groups according to disease severity. The main therapeutic goal with ECRS is to eliminate or diminish the bulk of NP tissue. NPs are unique abnormal lesions that grow from the lining of the nasal and paranasal sinuses, and type 2 inflammation plays a critical role in NP development in patients with ECRS. An imbalance between protease and endogenous protease inhibitors might play a pivotal role in the initiation and exacerbation of type 2 inflammation in ECRS. Intraepithelial mast cells in NPs, showing a tryptase+, chymase- phenotype, may also enhance type 2 inflammation. Intense edema and reduced fibrosis are important histological features of eosinophilic NPs. Mucosal edema mainly consists of exuded plasma protein, and excessive fibrin deposition would be expected to contribute to the retention of proteins from capillaries and thereby perpetuate mucosal edema that may play an etiological role in NPs. Upregulation of the coagulation cascade and downregulation of fibrinolysis strongly induce abnormal fibrin deposition in nasal mucosa, and type 2 inflammation plays a central role in the imbalance of coagulation and fibrinolysis. Topics: Chronic Disease; Eosinophils; Fibrin; Humans; Immunity, Innate; Inflammation; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis | 2020 |
Therapeutics targeting the fibrinolytic system.
The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed. Topics: Animals; Antifibrinolytic Agents; Fibrin; Fibrinolysis; Humans; Inflammation; Neoplasms; Thrombosis | 2020 |
Coagulopathy in COVID-19.
The COVID-19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID-19. The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial-sepsis-associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID-19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID-19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain. Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; COVID-19; Cytokines; Disseminated Intravascular Coagulation; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Hemorrhage; Hemostasis; Humans; Inflammation; Lung; Lymphocytes; Partial Thromboplastin Time; Protease Inhibitors; Prothrombin Time; Sepsis; Thrombosis | 2020 |
Primary central nervous system lymphomas associated with chronic inflammation: diagnostic pitfalls of central nervous system lymphomas.
In recent years, the features of lymphomas associated with chronic inflammation, referred to as diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation (DLBCL-CI), have been elucidated. DLBCL-CI is an aggressive lymphoma occurring in the context of long-standing chronic inflammation and showing an association with Epstein-Barr virus. Fibrin-associated diffuse large B-cell lymphoma (F-DLBCL) was suggested as a new and unusual form of DLBCL-CI in the most recent version of the World Health Organization classification. From the perspective of genetics, DLBCL-CI was associated with frequent TP53 mutation, MYC amplification and complex karyotypes, but cases of F-DLBCL behaved indolently and showed a relatively lower genetic complexity. In the central nervous system (CNS), several examples of DLBCL-CI and F-DLBCL have been reported. As with DLBCL-CI outside the CNS, DLBCL-CI in the CNS is an aggressive lymphoma. However, the clinical outcome of F-DLBCL in the CNS is good. Immunohistochemistry for p53 and c-Myc in DLBCL-CI and F-DLBCL in the CNS showed similar findings of those outside the CNS. However, one aggressive case showed transitional genetics and morphology between F-DLBCL and DLBCL-CI. These findings suggest that some cases of F-DLBCL in the CNS might have the potential to progress to DLBCL-CI. Topics: Aged; Aged, 80 and over; Central Nervous System Neoplasms; Disease Progression; Fibrin; Humans; Inflammation; Lymphoma, Large B-Cell, Diffuse; Mutation; Proto-Oncogene Proteins c-myc; Tumor Suppressor Protein p53 | 2020 |
Functional significance of the platelet immune receptors GPVI and CLEC-2.
Although platelets are best known for their role in hemostasis, they are also crucial in development, host defense, inflammation, and tissue repair. Many of these roles are regulated by the immune-like receptors glycoprotein VI (GPVI) and C-type lectin receptor 2 (CLEC-2), which signal through an immunoreceptor tyrosine-based activation motif (ITAM). GPVI is activated by collagen in the subendothelial matrix, by fibrin and fibrinogen in the thrombus, and by a remarkable number of other ligands. CLEC-2 is activated by the transmembrane protein podoplanin, which is found outside of the vasculature and is upregulated in development, inflammation, and cancer, but there is also evidence for additional ligands. In this Review, we discuss the physiological and pathological roles of CLEC-2 and GPVI and their potential as targets in thrombosis and thrombo-inflammatory disorders (i.e., disorders in which inflammation plays a critical role in the ensuing thrombosis) relative to current antiplatelet drugs. Topics: Amino Acid Motifs; Animals; Collagen; Extracellular Matrix; Fibrin; Fibrinogen; Humans; Inflammation; Lectins, C-Type; Membrane Glycoproteins; Neoplasm Proteins; Neoplasms; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Thrombosis | 2019 |
Tumors: Wounds That Do Not Heal-A Historical Perspective with a Focus on the Fundamental Roles of Increased Vascular Permeability and Clotting.
Similarities between solid tumor stroma generation, wound healing, chronic inflammation, and associated inflammatory diseases have prompted interest from the time of Virchow. However, it was not until the 1970s that these entities were shown to share important molecular mechanisms. Foundational to all of them is the initiating role of vascular endothelial growth factor (VEGF-A) in increasing vascular permeability to plasma and plasma proteins. Extravasated plasma activates the tissue factor clotting pathway, leading to extravascular deposition of a fibrin gel. Fibrin serves initially as a provisional stroma that provides a favorable substrate for the attachment and migration of tumor cells, as well as host fibroblasts, endothelial, and inflammatory cells. Fibrin and its degradation products have proangiogenic activity with important roles in the generation of new blood vessels and connective tissue stroma. Over time, fibrin is degraded and replaced by vascular and subsequently by dense, relatively avascular collagenous connective tissue, the end-product referred to as desmoplasia in tumors and scar in healed wounds. Fibrin and the mature stroma that replaces it provide a diffusion barrier to chemotherapy and a structural barrier that inflammatory cells must cross to reach tumor cells. Plasma solutes of varying size cross the endothelial cells lining capillaries and venules of normal tissues and "mother" vessels of tumors and wounds by different anatomical pathways. VEGF-A levels fall back to normal as wounds heal but remain perpetually elevated in solid tumors. Thus, tumors may heal centrally but continually initiate new healing activity as they grow and invade surrounding normal tissues. Topics: Capillary Permeability; Fibrin; Humans; Inflammation; Neoplasms; Thrombosis; Wound Healing | 2019 |
The blood compatibility challenge. Part 3: Material associated activation of blood cascades and cells.
Following protein adsorption/activation which is the first step after the contact of material surfaces and whole blood (part 2), fibrinogen is converted to fibrin and platelets become activated and assembled in the form of a thrombus. This thrombus formation is the key feature that needs to be minimized in the creation of materials with low thrombogenicity. Further aspects of blood compatibility that are important on their own are complement and leukocyte activation which are also important drivers of thrombus formation. Hence this review summarizes the state of knowledge on all of these cascades and cells and their interactions. For each cascade or cell type, the chapter distinguishes statements which are in widespread agreement from statements where there is less of a consensus. STATEMENT OF SIGNIFICANCE: This paper is part 3 of a series of 4 reviews discussing the problem of biomaterial associated thrombogenicity. The objective was to highlight features of broad agreement and provide commentary on those aspects of the problem that were subject to dispute. We hope that future investigators will update these reviews as new scholarship resolves the uncertainties of today. Topics: Adsorption; Animals; Biocompatible Materials; Blood Coagulation; Blood Platelets; Complement System Proteins; Fibrin; Fibrinogen; Hemolysis; Humans; Inflammation; Leukocytes; Materials Testing; Microspheres; Platelet Adhesiveness; Surface Properties; Thrombosis | 2019 |
The Duality of Fgl2 - Secreted Immune Checkpoint Regulator Versus Membrane-Associated Procoagulant: Therapeutic Potential and Implications.
Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. The biological importance of Fgl2 is evident within viral-induced fibrin depositing inflammatory diseases and malignancies and provides a compelling rationale for Fgl2 expression to not only be considered as a disease biomarker but also as a therapeutic target. This article will provide a comprehensive review of the currently known biological properties of Fgl2 and clarifies future scientific directives. Topics: Animals; Biomarkers; Blood Coagulation; Costimulatory and Inhibitory T-Cell Receptors; Fibrin; Fibrinogen; Glioblastoma; Humans; Immunosuppressive Agents; Inflammation; Lymphocyte Activation; T-Lymphocytes, Regulatory | 2016 |
The plasminogen activation system in neuroinflammation.
The plasminogen activation (PA) system consists in a group of proteases and protease inhibitors regulating the activation of the zymogen plasminogen into its proteolytically active form, plasmin. Here, we give an update of the current knowledge about the role of the PA system on different aspects of neuroinflammation. These include modification in blood-brain barrier integrity, leukocyte diapedesis, removal of fibrin deposits in nervous tissues, microglial activation and neutrophil functions. Furthermore, we focus on the molecular mechanisms (some of them independent of plasmin generation and even of proteolysis) and target receptors responsible for these effects. The description of these mechanisms of action may help designing new therapeutic strategies targeting the expression, activity and molecular mediators of the PA system in neurological disorders involving neuroinflammatory processes. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. Topics: Animals; Blood-Brain Barrier; Central Nervous System Diseases; Fibrin; Fibrinolysin; Humans; Inflammation; Leukocytes; Microglia; Plasminogen; Tissue Plasminogen Activator | 2016 |
Healing or Not Healing.
Healing process might be considered as a byproduct of the mechanisms underlying the biological defense system consisting of hemostasis and clotting, the innate immune system, and fibrogenesis. But there is no biological process that does not potentially entail high costs through trade-offs with other life-history parameters and that might be seen as collateral damage. Depending on the balance among the robust and flexible modular defense system, which will be deployed in many different arrays, the structural outcome of the healing process will not resolve with a unitary outcome. Drawing on the regenerative potential of platelets, plasma biomolecules and fibrin matrix, several systems of producing autologous platelets-and plasma derived products (APPDPs) have been developed and aimed at enhancing the natural in vivo tissue regenerative capacity of damaged tissues. Despite the care with which the medical staff elaborate and apply autologous platelets-and plasma derived products, some pitfalls arise regarding the composition of autologous plasma-and platelet derived products, the modalities of their application, and the in vitro versus in vivo evaluations, all of which can deeply influence tissue healing - a process which is already unpredictable, without a unitary mechanism that might be deployed in many different structural and functional arrays which culminate in the tissue repair. A biological approach to the application of autologous platelets-and plasma derived products is crucial to obtaining optimum functional healing outcomes in addition to avoiding poor clinical results and reaching misleading conclusions. Topics: Animals; Blood Platelets; Fibrin; Humans; Immunity, Innate; Inflammation; Macrophages; Wound Healing | 2016 |
What Is the Biological and Clinical Relevance of Fibrin?
As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery. Topics: Animals; Fibrin; Fibrinogen; Hemorrhage; Hemostasis; Humans; Infections; Inflammation; Mice; Mice, Knockout; Wound Healing; Wounds and Injuries | 2016 |
The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen).
Although the two phenomena are usually studied separately, we summarise a considerable body of literature to the effect that a great many diseases involve (or are accompanied by) both an increased tendency for blood to clot (hypercoagulability) and the resistance of the clots so formed (hypofibrinolysis) to the typical, 'healthy' or physiological lysis. We concentrate here on the terminal stages of fibrin formation from fibrinogen, as catalysed by thrombin. Hypercoagulability goes hand in hand with inflammation, and is strongly influenced by the fibrinogen concentration (and vice versa); this can be mediated via interleukin-6. Poorly liganded iron is a significant feature of inflammatory diseases, and hypofibrinolysis may change as a result of changes in the structure and morphology of the clot, which may be mimicked in vitro, and may be caused in vivo, by the presence of unliganded iron interacting with fibrin(ogen) during clot formation. Many of these phenomena are probably caused by electrostatic changes in the iron-fibrinogen system, though hydroxyl radical (OH˙) formation can also contribute under both acute and (more especially) chronic conditions. Many substances are known to affect the nature of fibrin polymerised from fibrinogen, such that this might be seen as a kind of bellwether for human or plasma health. Overall, our analysis demonstrates the commonalities underpinning a variety of pathologies as seen in both hypercoagulability and hypofibrinolysis, and offers opportunities for both diagnostics and therapies. Topics: Animals; Blood Coagulation; Computer Simulation; Fibrin; Fibrinogen; Fibrinolysis; Humans; Inflammation; Iron; Models, Immunological; Thrombophilia | 2015 |
Tumors: wounds that do not heal-redux.
Similarities between tumors and the inflammatory response associated with wound healing have been recognized for more than 150 years and continue to intrigue. Some years ago, based on our then recent discovery of vascular permeability factor (VPF)/VEGF, I suggested that tumors behaved as wounds that do not heal. More particularly, I proposed that tumors co-opted the wound-healing response to induce the stroma they required for maintenance and growth. Work over the past few decades has supported this hypothesis and has put it on a firmer molecular basis. In outline, VPF/VEGF initiates a sequence of events in both tumors and wounds that includes the following: increased vascular permeability; extravasation of plasma, fibrinogen and other plasma proteins; activation of the clotting system outside the vascular system; deposition of an extravascular fibrin gel that serves as a provisional stroma and a favorable matrix for cell migration; induction of angiogenesis and arterio-venogenesis; subsequent degradation of fibrin and its replacement by "granulation tissue" (highly vascular connective tissue); and, finally, vascular resorption and collagen synthesis, resulting in the formation of dense fibrous connective tissue (called "scar tissue" in wounds and "desmoplasia" in cancer). A similar sequence of events also takes place in a variety of important inflammatory diseases that involve cellular immunity. Topics: Blood Coagulation; Cell Movement; Fibrin; Hemostasis; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Stromal Cells; Vascular Endothelial Growth Factor A; Wound Healing | 2015 |
Viscoelasticity and Ultrastructure in Coagulation and Inflammation: Two Diverse Techniques, One Conclusion.
The process of blood clotting has been studied for centuries. A synopsis of current knowledge pertaining to haemostasis and the blood components, including platelets and fibrin networks which are closely involved in coagulation, are discussed. Special emphasis is placed on tissue factor (TF), calcium and thrombin since these components have been implicated in both the coagulation process and inflammation. Analysis of platelets and fibrin morphology indicate that calcium, tissue factor and thrombin at concentrations used during viscoelastic analysis (with thromboelastography or TEG) bring about alterations in platelet and fibrin network ultrastructure, which is similar to that seen in inflammation. Scanning electron microscopy indicated that, when investigating platelet structure in disease, addition of TF, calcium or thrombin will mask disease-induced alterations associated with platelet activation. Therefore, washed platelets without any additives is preferred for morphological analysis. Furthermore, morphological and viscoelastic analysis confirmed that thrombin activation is the preferred method of fibrin activation when investigating fibrin network ultrastructure. Topics: Animals; Blood Coagulation; Blood Platelets; Blood Viscosity; Elasticity; Fibrin; Humans; Inflammation; Microscopy, Electron, Scanning; Platelet Activation; Thrombelastography | 2015 |
Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases.
Most non-communicable diseases involve inflammatory changes in one or more vascular systems, and there is considerable evidence that unliganded iron plays major roles in this. Most studies concentrate on biochemical changes, but there are important biophysical correlates. Here we summarize recent microscopy-based observations to the effect that iron can have major effects on erythrocyte morphology, on erythrocyte deformability and on both fibrinogen polymerization and the consequent structure of the fibrin clots formed, each of which contributes significantly and negatively to such diseases. We highlight in particular type 2 diabetes mellitus, ischemic thrombotic stroke, systemic lupus erythematosus, hereditary hemochromatosis and Alzheimer's disease, while recognizing that many other diseases have co-morbidities (and similar causes). Inflammatory biomarkers such as ferritin and fibrinogen are themselves inflammatory, creating a positive feedback that exacerbates disease progression. The biophysical correlates we describe may provide novel, inexpensive and useful biomarkers of the therapeutic benefits of successful treatments. Topics: Blood Coagulation; Erythrocyte Deformability; Erythrocytes; Fibrin; Humans; Inflammation; Iron; Microscopy, Atomic Force | 2014 |
Biomaterial scaffolds used for the regeneration of spinal cord injury (SCI).
This review presents a summary of various types of scaffold biomaterials used alone or together with therapeutic drugs and cells to regenerate spinal cord injury (SCI). The inhibitory environment and loss of axonal connections after SCI give rise to critical obstacles to regeneration of lost tissues and neuronal functions. Biomaterial scaffolds can provide a bridge to connect lost tissues, an adhesion site for implanted or host cells, and sustained release of therapeutic drugs in the injured spinal cord. In addition, they not only provide a structural platform, but can play active roles by inhibiting apoptosis of cells, inflammation and scar formation, and inducing neurogenesis, axonal growth and angiogenesis. Many synthetic and natural biomaterial scaffolds have been extensively investigated and tested in vitro and in animal SCI models for these purposes. We summarized the literature on the biomaterials commonly used for spinal cord regeneration in terms of historical backgrounds and current approaches. Topics: Alginates; Animals; Apoptosis; Axons; Biocompatible Materials; Chitosan; Collagen; Disease Models, Animal; Drug Delivery Systems; Fibrin; Humans; Hyaluronic Acid; Inflammation; Lactic Acid; Materials Testing; Peptides; Polyesters; Polymers; Sepharose; Spinal Cord; Spinal Cord Injuries; Spinal Cord Regeneration; Stem Cells; Tissue Engineering; Tissue Scaffolds | 2014 |
Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation.
Fibrinogen and factor XIII are two essential proteins that are involved directly in fibrin gel formation as the final step of a sequence of reactions triggered by a procoagulant stimulus. Haemostasis is the most obvious function of the resulting fibrin clot. Different variables affect the conversion of fibrinogen to fibrin as well as the mode of fibrin polymerisation and fibrin crosslinking, hereby, critically influencing the architecture of the resulting fibrin network and consequently determining its mechanical strength and resistance against fibrinolysis. Due to fibrinogen's structure with a multitude of domains and binding motifs the fibrin gel allows for complex interactions with other coagulation factors, with profibrinolytic as well as antifibrinolyic proteins, with complement factors and with various cellular receptors. These interactions enable the fibrin network to control its own further state (i. e. expansion or degradation), to influence innate immunity, and to function as a scaffold for cell migration processes. During the whole process of fibrin gel formation biologically active peptides and protein fragments are released that additionally influence cellular processes via chemotaxis or by modulating cell-cell interactions. Thus, it is not surprising that fibrinogen and factor XIII in addition to their haemostatic function influence innate immunity as well as cell-mediated reactions like wound healing, response to tissue injury or inflammatory processes. The present review summarises current knowledge of fibrinogen's and factor XIII's function in coagulation and fibrinolysis giving special emphasis on their relation to inflammation control. Topics: Animals; Blood Coagulation; Cell Movement; Complement System Proteins; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Gene Expression Regulation; Hemostasis; Humans; Immunity, Innate; Inflammation; Integrins; Mice; Mice, Transgenic; Peptides; Protein Binding; Protein Structure, Tertiary | 2014 |
Coagulation and coagulation signalling in fibrosis.
Following tissue injury, a complex and coordinated wound healing response comprising coagulation, inflammation, fibroproliferation and tissue remodelling has evolved to nullify the impact of the original insult and reinstate the normal physiological function of the affected organ. Tissue fibrosis is thought to result from a dysregulated wound healing response as a result of continual local injury or impaired control mechanisms. Although the initial insult is highly variable for different organs, in most cases, uncontrolled or sustained activation of mesenchymal cells into highly synthetic myofibroblasts leads to the excessive deposition of extracellular matrix proteins and eventually loss of tissue function. Coagulation was originally thought to be an acute and transient response to tissue injury, responsible primarily for promoting haemostasis by initiating the formation of fibrin plugs to enmesh activated platelets within the walls of damaged blood vessels. However, the last 20years has seen a major re-evaluation of the role of the coagulation cascade following tissue injury and there is now mounting evidence that coagulation plays a critical role in orchestrating subsequent inflammatory and fibroproliferative responses during normal wound healing, as well as in a range of pathological contexts across all major organ systems. This review summarises our current understanding of the role of coagulation and coagulation initiated signalling in the response to tissue injury, as well as the contribution of uncontrolled coagulation to fibrosis of the lung, liver, kidney and heart. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. Topics: Blood Coagulation; Fibrin; Fibrosis; Humans; Inflammation; Wound Healing | 2013 |
Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation.
Inorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated. Topics: Animals; Blood Coagulation; Blood Platelets; Fibrin; Hemostasis; Humans; Inflammation; Models, Biological; Platelet Adhesiveness; Polyphosphates; Signal Transduction; Thrombin | 2012 |
Inflammation and coagulation. An overview.
Inflammation and coagulation are two main host-defence systems that interact with each other. Inflammation activates coagulation and coagulation modulates the inflammatory activity in many ways. The contributing molecular pathways are reviewed. Thrombin and activated protein C (APC) and its receptor EPCR constitute a major physiological regulatory system to control vascular wall permeability during sepsis. Pro-inflammatory cellular effects of coagulation proteases as well as the anti-inflammatory effects of APC/EPCR are mediated by signaling via protease activated receptors PAR on mononuclear cells, endothelial cells, platelets, fibroblast, and smooth muscle cells. The beneficial effects of APC in sepsis are mainly dependent on the PAR-mediated cell-protective properties rather than the anticoagulant protease function on coagulation cofactors FV/Va and FVIII/VIIIa. Animal experiments with signaling selective APC-variants show promise in improving the therapeutic efficacy and safety of APC in sepsis. Topics: Animals; Antithrombins; Blood Coagulation; Fibrin; Humans; Inflammation; Inflammation Mediators; Protein C; Receptors, Proteinase-Activated; Sepsis | 2011 |
Topical non-barrier agents for postoperative adhesion prevention in animal models.
Pelvic adhesion can form as a result of inflammation, endometriosis or surgical trauma. Most surgical procedures performed by obstetrician-gynecologists are associated with pelvic adhesions that may cause subsequent serious sequelae, including small bowel obstruction, infertility, chronic pelvic pain, and difficulty in postoperative treatment, including complexity during subsequent surgical procedures. An increasing number of adhesion reduction agents, in the form of site-specific and broad-coverage barriers and solutions, are becoming available to surgical teams. The most widely studied strategies include placing synthetic barrier agents between the pelvic structures. Most of the adhesions in the barrier-treated patients develop in uncovered areas in the abdomen. This fact suggests that the application of liquid or gel anti-adhesive agents to cover all potential peritoneal lesions, together with the use of barrier agents, may reduce the formation of postoperative adhesions. This article introduces the topical choices available for adhesion prevention mentioned in preliminary clinical applications and animal models. To date there is no substantial evidence that their use reduces the incidence of postoperative adhesions. In combination with good surgical techniques, these non-barrier agents may play an important role in adhesion reduction. Topics: Acetamides; Antioxidants; Collagen Type I; Female; Fibrin; Glucans; Glucose; Honey; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Icodextrin; Inflammation; Linezolid; Melatonin; Oxazolidinones; Pain, Postoperative; Pelvic Pain; Pelvis; Peritoneal Diseases; Phosphatidylcholines; Postoperative Complications; Tissue Adhesions; Treatment Outcome | 2010 |
Inflammation and coagulation.
In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation leads to activation of coagulation, and coagulation also considerably affects inflammatory activity. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Pro-inflammatory cytokines and other mediators are capable of activating the coagulation system and down-regulating important physiologic anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on expression of tissue factor and the simultaneous down-regulation of endothelial-bound anticoagulant mechanisms and endogenous fibrinolysis. Conversely, activated coagulation proteases may affect specific cellular receptors on inflammatory cells and endothelial cells and thereby modulate the inflammatory response. Topics: Antithrombins; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Down-Regulation; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Inflammation; Lipoproteins; Plasminogen; Protein C; Receptors, Proteinase-Activated; Thrombin | 2010 |
The plasminogen activation system in inflammation.
Inflammation is an adaptive response to damage of vascularized tissues, which develops according to a stereotyped sequence governed by the local production of the so-called "chemical mediators of inflammation". Here we review the evidences indicating a role of the plasminogen activation system in the regulation of all the phases of the inflammation process. Plasminogen activation controls the formation of complement anaphylotoxins (responsible for vasodilatation, increase of venular permeability and leukocyte chemotaxis) and of bradykinin (which accounts for vasodilatation, increase of venular permeability and pain) by regulating the plasma contact system. The urokinase plasminogen activator and its cellular receptor, expressed on the surface of human leukocytes, provide a functional unit that, by regulating interaction of leukocytes with extracellular matrix, as well as its degradation, is critical for the migration of leukocytes and for their movement in the damaged tissues. By preventing excess fibrin accumulation in inflamed tissues, the plasminogen activation system also governs the proper evolution of the inflammatory exudates and prevents the possibility of a shift from acute to chronic inflammation. Topics: Cell Movement; ErbB Receptors; Exudates and Transudates; Fibrin; Humans; Inflammation; Integrins; Kininogen, High-Molecular-Weight; Plasminogen Activators; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator | 2008 |
Angiogenesis and inflammation in carotid atherosclerosis.
Carotid atherosclerosis is a leading cause of cerebrovascular events. The control of cardiovascular risk factors, i.e. tobacco smoking, alcohol abuse, hypertension, dyslipidemia, diabetes and obesity proved to reduce number of fatal and non-fatal strokes but failed to prevent important number of them. Screening for biomarkers in individuals at high risk of symptomatic vascular disease helped to identify some of them. However, as disease is by its nature multifocal, global testing for biomarkers may have limited practical application. New imaging techniques, including direct visualization of artery metabolism, by 18-FDG-PET, has brought new tools to study local atherosclerosis progression and individual plaque metabolic activity. Advances in molecular biology helped to identify inflammatory genes and its strong link to angiogenesis. The later, is thought to play a key role in the transformation to unstable plaque. Studies of the complex role that plays angiogenesis in plaque development will help in future to design effective therapies addressed at the individual cell level. The purpose of the review is to bring new insights into complicated pathophysiology of carotid atherosclerosis. Topics: Biomarkers; C-Reactive Protein; Carotid Artery Diseases; Endothelium, Vascular; Fibrin; Fibrinogen; Humans; Inflammation; Neovascularization, Pathologic; Stroke; Tunica Intima | 2008 |
Cancer as an overhealing wound: an old hypothesis revisited.
What is the relationship between the wound-healing process and the development of cancer? Malignant tumours often develop at sites of chronic injury, and tissue injury has an important role in the pathogenesis of malignant disease, with chronic inflammation being the most important risk factor. The development and functional characterization of genetically modified mice that lack or overexpress genes that are involved in repair, combined with gene-expression analysis in wounds and tumours, have highlighted remarkable similarities between wound repair and cancer. However, a few crucial differences were also observed, which could account for the altered metabolism, impaired differentiation capacity and invasive growth of malignant tumours. Topics: Animals; Cicatrix; Epithelium; Extracellular Matrix; Fibrin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Models, Biological; Neoplasms; Neovascularization, Physiologic; Wound Healing | 2008 |
Biology of the peritoneum in normal homeostasis and after surgical trauma.
The peritoneum is a serous membrane, which has a protective function for the contents of the abdominal cavity. It maintains homeostasis by allowing exchange of molecules and production of peritoneal fluid, thus providing an environment in which intra-abdominal organs can function properly. When traumatized, whether by surgery or due to inflammatory processes, a series of responses come into action to regenerate the injured part of the peritoneum. The inflammatory reaction causes influx of inflammatory cells but also activates resident mesothelial cells, ultimately leading to a fibrinous exudate. Depending on the severity of the trauma this exudate is transient due to fibrinolysis, or becomes more dense as a result of fibroblasts persisting, leading to fibrinous adhesions. A pivotal role is taken by the enzyme plasmin and its promotors and inhibitors; it is mainly the tissue-type plasminogen activator/plasminogen activator inhibitor ratio which determines the rate of fibrinolysis and therefore the rate of adhesion formation. The rate of injury determines the rate and extent of the inflammatory response to that injury; in its turn the inflammatory reaction determines the extent of adhesion formation. One should realize this when performing intra-abdominal surgery, which is in fact operating inside the peritoneal organ. Topics: Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Homeostasis; Humans; Inflammation; Ischemia; Peritoneum; Postoperative Complications; Tissue Adhesions; Tissue Plasminogen Activator | 2007 |
Role of tissue factor in thrombosis. Coagulation-inflammation-thrombosis circuit.
Tissue factor (TF) plays a role in thrombogenesis. TF initiates blood coagulation resulting in the generation of protease coagulant mediators (FVIIa, FXa, and FIIa) and fibrin production. TF hypercoagulablility directly contributes to thrombus formation resulting from the major events of fibrin deposition and FIIa-induced platelet activation/aggregation. In addition, blood coagulation indirectly promotes thrombogenicity via the coagulation-inflammation cycle in which TF plays a diverging and converging role. As the consequence of coagulation-dependent inflammation in which protease-activated receptor (PAR) mediates the coagulant signaling to elicit cytokines, selectins, and growth factors, such inflammation facilitates thrombosis by platelet aggregation and leukocyte recruitment. As TF hypercoagulability concerned, anti-thrombotic strategies involve the prevention by anticoagulation and PAR antagonism. Anticoagulants block the direct and indirect thrombotic contributions, while PAR antagonists arrest coagulation-dependent inflammation. With respect to both thrombosis and inflammation being cardiovascular risk factors, such strategies offer diverse benefits to cardioprotection. Topics: Animals; Blood Coagulation; Blood Vessels; Cardiovascular Diseases; Factor VIIa; Factor Xa; Fibrin; Humans; Inflammation; Models, Biological; Myocardium; Peptides; Platelet Aggregation; Prothrombin; Receptors, Proteinase-Activated; Thromboplastin; Thrombosis | 2006 |
Pharmacological inhibition of tissue factor.
Tissue factor plays an essential role in the initiation of coagulation in vivo. In severe conditions, including sepsis and acute lung injury, increased expression of tissue factor may induce disseminated intravascular coagulation and fibrin deposition in organs, which are believed to have a determining impact on patient outcome. Tissue factor also acts as a signaling receptor and is involved in the systemic inflammatory response, as in cancer progression and atherosclerosis. Interventions aiming at limiting tissue factor activities have been evaluated in multiple experimental studies and the observed results have supported the potential benefits for coagulation disorders, inflammation, and survival. The effects of the main physiological inhibitor of tissue factor, tissue factor pathway inhibitor, have been evaluated in two large clinical trials in sepsis. Even though they are not associated with an improved outcome, the observed data support further clinical studies. Topics: Animals; Blood Coagulation; Clinical Trials as Topic; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Humans; Inflammation; Lipoproteins; Lung; Lung Injury; Sepsis; Signal Transduction; Thromboplastin | 2006 |
Fibrin(ogen) and its fragments in the pathophysiology and treatment of myocardial infarction.
The occlusion of a coronary artery leads to ischemia of the myocardium, while permanent occlusion results in cell death and myocardial dysfunction. Early restoration of blood flow is the only means to reduce or prevent myocardial necrosis, but-paradoxically-reperfusion itself contributes to injury of the heart. In animal models, this phenomenon is well described, and there are many different unrelated approaches to reduce reperfusion injury. In humans, however, pharmacological interventions have so far failed to reduce myocardial reperfusion injury. We summarize the pathogenesis of reperfusion injury, detailing the role of fibrin(ogen) and its derivatives. Moreover, we introduce a new concept for fibrin derivatives as potential targets for reperfusion therapy. Topics: Animals; Anti-Inflammatory Agents; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Inflammation; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium | 2006 |
Tissue factor mediates inflammation.
The role of tissue factor (TF) in inflammation is mediated by blood coagulation. TF initiates the extrinsic blood coagulation that proceeds as an extracellular signaling cascade by a series of active serine proteases: FVIIa, FXa, and thrombin (FIIa) for fibrin clot production in the presence of phospholipids and Ca2+. TF upregulation resulting from its enhanced exposure to clotting factor FVII/FVIIa often manifests not only hypercoagulable but also inflammatory state. Coagulant mediators (FVIIa, FXa, and FIIa) are proinflammatory, which are largely transmitted by protease-activated receptors (PAR) to elicit inflammation including the expression of tissue necrosis factor, interleukins, adhesion molecules (MCP-1, ICAM-1, VCAM-1, selectins, etc.), and growth factors (VEGF, PDGF, bFGF, etc.). In addition, fibrin, and its fragments are also able to promote inflammation. In the event of TF hypercoagulability accompanied by the elevations in clotting signals including fibrin overproduction, the inflammatory consequence could be enormous. Antagonism to coagulation-dependent inflammation includes (1) TF downregulation, (2) anti-coagulation, and (3) PAR blockade. TF downregulation and anti-coagulation prevent and limit the proceeding of coagulation cascade in the generation of proinflammatory coagulant signals, while PAR antagonists block the transmission of such signals. These approaches are of significance in interrupting the coagulation-inflammation cycle in contribution to not only anti-inflammation but also anti-thrombosis for cardioprotection. Topics: Anticoagulants; Blood Coagulation; Calcium; Cell Adhesion Molecules; Extracellular Signal-Regulated MAP Kinases; Fibrin; Humans; Inflammation; Interleukins; Phospholipids; Receptors, Proteinase-Activated; Serine Endopeptidases; Thromboplastin; Tumor Necrosis Factor-alpha | 2005 |
Mechanisms and mediators of pulmonary fibrosis.
The mechanisms of pulmonary fibrosis are complex, and several hypotheses have been put forward to explain how fibrosis develops. It was long thought that inflammation was a key event in the process; however, this has recently been challenged. The inflammation hypothesis has led to the description of numerous inflammatory and profibrotic mediators in the pathogenesis of fibrosis. Inhibition of inflammation can attenuate fibrosis in animal models but is less successful in humans. More recently, an important role for epithelial injury, circulating mesenchymal precursor cells, epithelial-to-mesenchymal transition, and vascular remodeling have been described in various models of fibrosis. Many of the classic inflammatory and profibrotic mediators are important in these processes, as well. The development of effective therapies will require the understanding of the complex interplay of the various mediators and the mechanisms of remodeling. Topics: Animals; Arachidonic Acid; Blood Coagulation Factors; Cytokines; Fibrin; Growth Substances; Humans; Inflammation; Inflammation Mediators; Lipids; Pulmonary Fibrosis | 2005 |
A new role in hemostasis for the adhesion receptor P-selectin.
The adhesion receptor P-selectin has long been known to support leukocyte rolling and emigration at sites of inflammation. Recently, P-selectin was also revealed to be a key molecule in hemostasis and thrombosis, mediating platelet rolling, generating procoagulant microparticles containing active tissue factor and enhancing fibrin deposition. Elevated levels of plasma P-selectin are indicative of thrombotic disorders and predictive of future cardiovascular events. Because the interaction between P-selectin and its receptor P-selectin glycoprotein ligand-1 (PSGL-1) represents an important mechanism by which P-selectin induces the formation of procoagulant microparticles and recruits the microparticles to thrombi, anti-thrombotic strategies are currently aimed at inhibiting this interaction. Recent developments also suggest that the procoagulant potential of P-selectin could be used to treat coagulation disorders such as hemophilia A. Topics: Animals; Blood Coagulation Disorders; Cardiovascular Diseases; Cell Adhesion; Fibrin; Humans; Inflammation; Leukocytes; Membrane Glycoproteins; Mice; Models, Biological; P-Selectin; Phenotype; Protein Binding; Protein Structure, Tertiary; Thromboplastin; Thrombosis | 2004 |
[Tissue factor expression at the site of inflammation: a cross-talk between inflammation and the blood coagulation system].
Recent studies have revealed a close association of the blood coagulation system with inflammation and immune reactions. The products of the cascade reaction of blood coagulation can work as inflammatory mediators or immune modulators, and, vice versa, some inflammatory or immune stimuli are linked to induction of blood coagulation. First, tissue factor (the blood coagulation initiator), the monocyte/macrophage tissue factor expression regulatory factors associated with inflammation and immune reactions, and the assembly of coagulation factors on leukocytes were reviewed. Second, evidence of leukocyte tissue factor expression and subsequent fibrin deposition were demonstrated at sites of infection or allergic reactions, using immunohistochemical staining. Third, the progress in the investigation of thrombin was reviewed from the viewpoint of its effects on inflammation (vascular permeability enhancement, leukocyte chemotaxis, chemical mediator release, etc.) and immune reactions (T-cell proliferation, cytokine production, etc.). The evidence presented here indicates a cross-talk between blood coagulation and inflammatory and immune reactions, suggesting that the products of the clotting reaction (e.g., thrombin) in lesions are real-time markers of inflammatory diseases. Topics: Biomarkers; Blood Coagulation; Fibrin; Humans; Inflammation; Inflammation Mediators; Thrombin; Thromboplastin | 2004 |
Fibrin mechanisms and functions in nervous system pathology.
In brain physiology, cerebrovascular interactions regulate both, vascular functions, such as blood vessel branching and endothelial cell homeostasis, as well as neuronal functions, such as local synaptic activity and adult neurogenesis. In brain pathology, including stroke, HIV encephalitis, Alzheimer Disease, multiple sclerosis, bacterial meningitis, and glioblastomas, rupture of the vasculature allows the entry of blood proteins into the brain with subsequent edema formation and neuronal damage. Fibrin is a blood-derived protein that is not produced by cells of the nervous system, but accumulates only after disease associated with vasculature rupture. This review presents evidence from human disease and animal models that highlight the role of fibrin in nervous system pathology. Our review presents novel experimental data that extend the role of fibrin, from that of a blood-clotting protein in cerebrovascular pathologies, to a component of the perivascular extracellular matrix that regulates inflammatory and regenerative cellular responses in neurodegenerative diseases. Topics: Amino Acid Sequence; Ancrod; Animals; Blood-Brain Barrier; Fibrin; Fibrinogen; Fibrinolytic Agents; Homeostasis; Humans; Inflammation; Macrophages; Molecular Sequence Data; Multiple Sclerosis; Myelin Sheath; Nerve Regeneration; Nervous System; Neuroglia; Neurons; Signal Transduction | 2004 |
Nervous system pathology: the fibrin perspective.
Studies of extracellular matrix (ECM) biology in the nervous system have mainly focused on laminin, fibronectin and tenascin-R, proteins that are present during nervous system development and normal function. However, during disease, fibrin, which physiologically is not present in the nervous tissue, is detected at nervous tissue lesions. This review summarizes evidence that correlates fibrin deposition with neuropathology and presents recent findings on cellular mechanisms and intracellular signaling pathways regulated by fibrin that might contribute to nervous system disease. Topics: Animals; Fibrin; Humans; Inflammation; Nervous System; Nervous System Diseases; Signal Transduction | 2002 |
Histopathologic alterations after endovascular radiation and antiproliferative stents: similarities and differences.
Endovascular radiation and drug-eluting antiproliferative stents in experimental animals (normal pigs and rabbit arteries) show a decrease in the neointimal growth at 1 month vs. controls. However, this is accompanied by delayed healing characterized by persistence of neointimal fibrin (with or without inflammation), a decrease in smooth muscle cells, and incomplete endothelialization. Conversely, stainless steel control stents show complete healing with the neointima consisting of smooth muscle cells in a proteoglycan-collagen matrix and near complete luminal surface endothelialization.. Long-term (3 and 6 months) animal studies fail to show any benefit with radiation or drug-eluting stents. These experimental results are discrepant from those seen clinically in man where both therapies have shown benefit at 6 months, suggesting that animal data may not be predictive of clinical results. The main differences can be explained on the basis of preclinical studies performed in juvenile animals without underlying atherosclerosis, which leads to accelerated healing in animals vs. man such that 1 month animal data likely correspond to 6 months in man. Therefore long-term (24-30 months) angiographic and/or IVUS follow-up studies in man will be required to determine if drug-eluting stents will behave similarly to animal studies at 3 and 6 months. Topics: Animals; Antineoplastic Agents, Phytogenic; Brachytherapy; Coronary Restenosis; Coronary Vessels; Fibrin; Follow-Up Studies; Humans; Iliac Artery; Inflammation; Microscopy, Electron, Scanning; Paclitaxel; Platelet Aggregation; Rabbits; Radiation-Sensitizing Agents; Stainless Steel; Stents; Swine; Thrombosis | 2002 |
Microvascular coagulopathy and disseminated intravascular coagulation.
To review the dual characteristics of disseminated intravascular coagulation (DIC), as both a contributor to multiple organ failure as well as a symptom of severe underlying disease associated with systemic vascular changes.. Published literature data and unpublished results from the authors.. Clinical and experimental studies strongly suggest that DIC contributes to multiple organ failure and death in patients with severe systemic disorders such as sepsis. DIC is evoked by systemic cytokine activity, and the inflammatory response aggravates vascular permeability, inflammation, and cell damage in tissues. In addition to intravascular fibrin formation, thrombin and fibrin generation in tissues is also an important aspect of DIC. An example of DIC at the organ level is adult respiratory distress syndrome, where fibrin in the lung is a characteristic feature. Intravascular fibrin formation and occlusion may elicit a hypoxic response with induction of hypoxia related transcription factors. The resulting ischemic preconditioning may offer protective effects to the involved organ(s).. Overall, the beneficial or harmful effects of activated coagulation and fibrin formation for organ pathology and recovery from DIC remain to be explored. This may be a critical element in the assessment of ischemia-reperfusion effects of specific anticoagulant therapy. Topics: Anticoagulants; Capillary Permeability; Cytokines; Disseminated Intravascular Coagulation; Endothelium, Vascular; Fibrin; Humans; Inflammation; Microcirculation; Multiple Organ Failure; Respiratory Distress Syndrome; Sepsis; Thrombin | 2001 |
[Treatment of anterior segment fibrinous reactions and hemorrhage with intracameral low dose rt-PA: clinical study and review of the literature].
to evaluate the efficacy and the safety of low dose intraocular tissue plasminogen activator (rt-PA) in the treatment of traumatic hyphema and postoperative fibrinous membrane.. Six microg to 10 microg of rt-PA was injected into the anterior chamber to treat severe fibrinous postoperative membranes and total traumatic hyphemae.. Thirteen eyes of 13 patients were treated. Four cases of traumatic hyphema and 9 cases of fibrinous membranes were included. Complete fibrinolysis within 24 hours was observed in 4 cases (30.8%). A partial success was noted in 7 eyes (53.8%). No beneficial effect was observed in two cases of traumatic hyphema associated with intravitreal hemorrhage after penetrating trauma. No side effect attributable to rt-PA occurred.. Low dose intraocular rt-PA appears to be safe and effective in the treatment of postoperative fibrinous membrane and endocular hemorrhage limited to the anterior chamber. Topics: Adolescent; Adult; Aged; Child; Eye Injuries; Female; Fibrin; Fibrinolytic Agents; Humans; Hyphema; Inflammation; Male; Middle Aged; Ophthalmologic Surgical Procedures; Postoperative Complications; Recombinant Proteins; Tissue Plasminogen Activator | 2000 |
Inflammatory processes in a murine model of intra-abdominal abscess formation.
Abscess formation has been viewed as a host defense strategy to contain the spread of infection. However, abscesses are also serious and life-threatening manifestations of persisting microbial infection. The initiation of abscess formation, both clinically and experimentally, involves the release of bacteria and an abscess-potentiating agent (e.g., fecal fiber or an analog) into a sterile site, with host defense mechanisms being unable to eliminate the infecting organisms. Abscess formation is aided by a combination of factors that share a common feature: impairment of phagocytic killing and hence clearance of microorganisms. These include bacterial virulence factors (e.g., capsule formation, succinic acid production); complement activation by the abscess potentiating agent; fibrin deposition; and microbial sequestration within abscess neutrophils. Recruitment of cells into the peritoneal cavity follows mast cell activation in the pathogenesis of infection: histamine and tumor necrosis factor alpha can be detected in the peritoneal cavity within minutes of challenge with an abscess-inducing mixture. However, the role of mast cells in host defense is made less clear by the finding of diminished abscess formation (but no mortality or increased morbidity) in mast-cell-depleted mice. This may indicate that mast cell products have a role in not only the initiation of an inflammatory response but also the promotion of fibrin deposition and abscess formation. Topics: Abdominal Abscess; Animals; Disease Models, Animal; Fibrin; Humans; Inflammation; Mast Cells; Mice; Sepsis; Time Factors | 1999 |
Role of fibrin and plasminogen activators in repair-associated angiogenesis: in vitro studies with human endothelial cells.
Angiogenesis, the formation of new blood vessels from existing ones, plays a central role in development and in a number of pathological conditions. Tissue repair-associated angiogenesis usually involves cell invasion into a fibrin structure and the presence of inflammatory cells. In this chapter the role of plasminogen activators in the dissolution of fibrin and the invasion of endothelial cells into a fibrin matrix is described. Tissue-type plasminogen activator is stored in endothelial cells and can be released acutely into the vessel lumen upon stimulation of the endothelium to activate fibrinolysis and to prevent fibrin deposition. At the basolateral side of the cell, urokinase-type plasminogen activator (uPA) bound to a specific cellular receptor is involved in the proteolytic modulation of matrix proteins and cell-matrix interaction. The cytokine tumor necrosis factor-alpha (TNF-alpha) cooperates with the angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in inducing human microvascular endothelial cells in vitro to invade a three dimensional fibrin matrix and to form capillary-like tubular structures. The formation of these capillary-like tubules requires cell-bound uPA activity. Topics: Animals; Endothelial Growth Factors; Endothelium, Vascular; Fibrin; Fibrinolysis; Fibroblast Growth Factor 2; Growth Substances; Humans; Inflammation; Lymphokines; Metalloendopeptidases; Microcirculation; Neovascularization, Pathologic; Neovascularization, Physiologic; Plasminogen Activators; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Tumor Necrosis Factor-alpha; Urokinase-Type Plasminogen Activator; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors | 1997 |
The role of fibrinolysis in adhesion formation.
Postsurgical abdominal adhesions and their sequelae continue to present major clinical and medicoeconomic problems. A complex network of mediators and responses affecting at least five interrelated biological systems, including the fibrinolytic system, are involved in the pathogenesis of postsurgical adhesions. The fibrinolytic system degrades fibrin through the action of the enzyme plasmin, which is stored as the inactive substrate plasminogen. Fibrinolysis, by mediating fibrin degradation, appears to play a pivotal role in adhesiogenesis. Tissue-type plasminogen activator (tPA) is the chief plasminogen activator in the blood, but its activity is restricted by plasminogen activating inhibitors type 1 (PAI-1) and type 2 (PAI-2). Inadequate peritoneal fibrinolysis may result from decreased tPA, increased PAI-1 and PAI-2, or both. The causal relationship between a reduction in fibrinolytic capacity and the formation of adhesions has been demonstrated in animals. In human studies, plasminogen activator activity (PAA) was significantly reduced in peritoneal biopsies from patients with peritonitis compared with those from normal patients. During surgery, PAA declined significantly in both normal and inflamed peritoneum. tPA was responsible for about 95% of PAA. Reduced fibrinolysis in human peritoneum associated with peritonitis and abdominal surgery correlates with increased adhesion formation and may thus be an important early biochemical event leading to adhesion formation. The regulation of plasmin-mediated fibrin degradation in the peritoneal cavity is poorly understood. However, new insights in the cellular distribution of fibrinolytic components in peritoneal tissue suggest that the mesothelium appears to have a principal role in fibrin regulation in the peritoneal cavity and in the early formation of adhesions. Topics: Animals; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Inflammation; Peritoneum; Postoperative Complications; Tissue Adhesions; Tissue Plasminogen Activator | 1997 |
Tissue factor pathway.
Blood coagulation is initiated in response to vessel damage in order to preserve the integrity of the mammalian vascular system. The coagulation cascade can also be initiated by mediators of the inflammatory response, and fibrin deposition has been noted in a variety of pathological states. The cascade of coagulation zymogen activations which leads to clot formation is initiated by exposure of flowing blood to tissue factor (TF), the cellular receptor and cofactor for factor VII (FVII). FVII binds to the receptor in a 1:1 stoichiometric complex and is rapidly activated. FVIIa undergoes an active site transition upon binding TF in the presence of calcium which enhances the fundamental properties of the enzyme. This results in rapid autocatalytic activation of FVII to VIIa thereby amplifying the response by generating more TF-VIIa complexes. The TF-VIIa activates both FIX and FX. Further FXa generation by the IXa-VIIIa-Ca(2+)-phospholipid complex is required to sustain the coagulation mechanism, since the TF-VIIa complex is rapidly inactivated. Structure and function studies have identified a number of regions on both TF and FVII involved in this interaction. It is clear, however, that the molecular structures of TF, FVII and the TF-VII complex will have to be solved before we fully understand this complex interaction. The activity of the TF-VIIa complex is controlled by two inhibitors:tissue factor pathway inhibitor (TFPI) and antithrombin III (AT-III). TFPI circulates in plasma, is associated with vascular cell surface and is released from platelets following stimulation by thrombin. TFPI requires the formation of an active TF-VIIa complex and FXa generation before inhibition can occur. Similarly, AT-III which is unable to inhibit circulating FVIIa requires the formation of the TF-VIIa complex. TFPI prevents further participation of TF in the coagulation process by forming a stable quaternary complex, TF-VIIa-Xa-TFPI. In contrast, the AT-III-VIIa complex is thought to dissociate from TF allowing it to interact with additional FVII-VIIa. TFPI has been considered the primary regulator of TF-VIIa activity during haemostasis. Whether AT-III in the presence of glycosaminoglycans on cell surfaces expressing TF can function as an auxiliary second physiological regulator is not known. Topics: Antithrombin III; Blood Coagulation; Blood Coagulation Factors; Endothelium, Vascular; Factor VII; Fibrin; Humans; Inflammation; Lipoproteins; Models, Molecular; Protein Binding; Protein Conformation; Thromboplastin | 1994 |
P-selectin and wound healing.
The history of the wound can by some accounts be traced nearly 5,000,000 years in the prehistoric ancestry of man (Majno, 1991). While there have been many descriptive accounts of the wound and wound healing over the centuries, in recent years rapid advances in the field of adhesion biology have added greatly to the understanding of the wound. Disruptions in the continuity of the vessel wall, whether by trauma or disease, induce a number of physiologic responses. The endothelium responds to fibrin contact in numerous ways including the rapid release of stored of von Willebrand factor and the expression of P-selectin upon the cell surface. Deposition of fibrin at the site of vascular injury serves other vital roles in the acute response to injury. Fibrin deposition stabilizes platelets as part of the development of a mural thrombus. Fibrin may also act to serve as a biological scaffold upon which inflammatory cells may adhere and participate in the acute response to injury. Finally, it is apparent that fibrin may act as a lattice upon which fibroblasts, smooth muscle cells and endothelial cells may adhere and migrate in order to return the vessel to its original state. In tumorigenesis, fibrinogen and fibrin may deposit in the perivascular space within the tumor and contribute by incompletely understood mechanisms to tumor growth and metastasis. The understanding of fibrin induced endothelial cell responses and how P-selectin and other endothelial cell adhesion molecules function in wound healing is important for understanding the vascular response to injury. Topics: Animals; Blood Platelets; Blood Vessels; Cell Adhesion Molecules; Endothelium, Vascular; Fibrin; Humans; Inflammation; P-Selectin; Platelet Membrane Glycoproteins; Wound Healing | 1993 |
Endothelial cell responses to fibrin mediated by FPB cleavage and the amino terminus of the beta chain.
Endothelial cells (EC) interact with fibrin at sites of vascular injury, thrombosis, inflammation and tumor growth, whereas they are quiescent when exposed to circulating fibrinogen. To determine the structural basis for specific interaction with fibrin we have characterized the response of EC to fibrin of varying structure. Fibrin was prepared with thrombin, which cleaves both fibrinopeptide A (FPA) and fibrinopeptide B (FPB), with Reptilase, which cleaves only FPA, and with contortrix procoagulant to cleave only FPB. Fibrin with FPB cleavage stimulated release of von Willebrand factor from EC Weibel-Palade bodies and also supported cell spreading. Involvement of the amino terminus of the fibrin beta chain in the response was shown by stimulation of von Willebrand factor release by the peptide beta 15-42. Also, fibrin prepared from a fibrinogen derivative lacking residues 15-42 of the beta chain failed to support EC spreading. EC adhesion was unaffected by the pattern of fibrinopeptide cleavage or by the removal of peptide beta 15-42 from fibrin. The results indicate that separate sites on the fibrin molecule mediate adhesion and spreading, and that the latter requires cleavage of FPB and the new amino terminus of the beta chain. They further suggest that cellular responses to fibrin are regulated by the proteolytic cleavages and conformational changes that convert fibrinogen to fibrin and may also be modulated by plasmic or elastase degradation. Topics: Amino Acid Sequence; Animals; Cell Adhesion; Endothelium, Vascular; Fibrin; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Humans; Inflammation; Macromolecular Substances; Molecular Sequence Data; Neoplasms; Platelet Adhesiveness; Thrombosis; von Willebrand Factor | 1993 |
Adhesions in gynecologic surgery.
The pathophysiology of adhesion formation continues to be perplexing. A delicate balance appears to exist between those wound factors that would initiate the physiologic process of peritoneal wound healing and those factors necessary for the lysis of fibrin, a major component of adhesions. Research continues to elucidate the roles of leukotrienes, prostaglandins, protein kinase-C, and transforming growth factors in adhesiogenesis. The ability to enhance plasmin's fibrinolytic activity or to impede plasminogen activator inhibitor factor may have important clinical ramifications in adhesiolysis. Clinical studies continue to address the effectiveness of intraperitoneal additives (dextran, lactated Ringer's solution, heparin) and barriers to adhesion formation (Interceed, TC7, Johnson & Johnson, New Brunswick, NJ; Gore-Tex, polytetrafluoroethylene, Gore & Assoc, Flagstaff, AZ). Surgical technique with attention to hemostasis, minimal trauma, proper suture selection, and peritoneal irrigation continues to be the mainstay in adhesion prevention. Topics: Anti-Inflammatory Agents, Non-Steroidal; Calcium; Female; Fibrin; Genital Diseases, Female; Humans; Inflammation; Poloxalene; Polytetrafluoroethylene; Tissue Adhesions | 1993 |
Growth factors and cutaneous wound repair.
The healing of an adult skin lesion is a well studied but complex affair of some considerable clinical interest. Endogenous growth factors, including the EGF, FGF, PDGF and TGF beta families, are released at the wound site and presumed to be a necessary part of the natural wound healing machinery. Moreover, members of each of these families have been shown to enhance healing if added exogenously to a wound site. In this review we shall briefly discuss what is known about the mechanics and cell biology of adult wound healing, describe the normal cellular source of growth factors during the healing process and, with reference to their known capacities in tissue culture, speculate as to how particular growth factors might be able to enhance healing. Topics: Animals; Cells, Cultured; Cicatrix; Connective Tissue; Epidermal Growth Factor; Fibrin; Fibroblast Growth Factors; Gene Expression Regulation; Growth Substances; Humans; Inflammation; Keratinocytes; Male; Mice; Platelet-Derived Growth Factor; Receptors, Cell Surface; Salivary Proteins and Peptides; Skin; Transforming Growth Factors; Wound Healing | 1992 |
The role of leukocytes in the activation of blood coagulation.
Topics: Blood Coagulation; Blood Coagulation Factors; Fibrin; Humans; Inflammation; Leukocytes; Monocytes | 1992 |
The specific interaction between fibrin(ogen) and hyaluronan: possible consequences in haemostasis, inflammation and wound healing.
We have proposed that fibrin and hyaluronan (HA) are macromolecular regulators during inflammation and wound healing. Here we extend our studies to characterize the specific interaction between fibrin(ogen) and HA. 125I-labelled HA (Mr approximately 32,000) was bound by plastic surfaces coated with human fibrinogen but not bovine serum albumin, ovalbumin, beta-lactoglobin or rabbit immunoglobulin G. 125I-labelled fibrinogen bound to a unique hexylamine derivative of HA coupled to Sepharose and was eluted specifically by HA oligosaccharides in a size-dependent manner. A dot blot assay, in which proteins are adsorbed to nitrocellulose and probed with 125I-HA, also showed specific binding to human fibrinogen. This assay was used to examine fibrinogens from other mammalian species. No specific 125I-HA binding was observed with the protein from horse, rat or cow. Significant binding was detected with human, sheep, rabbit, dog, baboon, goat and pig fibrinogens. Thrombin-induced formation of fibrin clots is also affected by HA, which decreases the lag time before clotting and increases the rate of clot formation. The rate of fibrin polymerization increased over 500% in the presence of 60 microM HA. Furthermore, the structure of the fibrin gel, as assessed by light scattering, was altered by HA or chondroitin sulphate in a concentration-dependent manner. The results support the proposed wound-healing model and indicate that an increase in circulating HA levels could adversely affect haemostasis and increase the risk of thrombosis or bleeding. The interaction between HA and fibrinogen emphasizes the importance of the liver endothelial cell HA receptor in the removal of glycosaminoglycans from the blood. Cultured cells continuously endocytosing 125I-HA for 4 h reutilized their total cellular HA receptors at least once every 50 min even in the presence of cycloheximide. This endocytotic receptor was therefore shown to be part of a recycling system. Topics: Animals; Fibrin; Fibrinogen; Hemostasis; Humans; Hyaluronic Acid; Inflammation; Wound Healing | 1989 |
Macrophage procoagulants.
From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders. Topics: Animals; Anti-Inflammatory Agents; Antigens; Blood Coagulation; Blood Coagulation Factors; Cell Line; Factor V; Factor VII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Guinea Pigs; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Infections; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; Neoplasms; Neutrophils; Rabbits; Rats; T-Lymphocytes; Thromboembolism; Thromboplastin; Warfarin | 1984 |
Blood tests for the diagnosis of venous and arterial thrombosis.
There are many reports in the literature of blood test abnormalities occurring in patients with venous or arterial thrombosis. Most of these have not used acceptable criteria for establishing an association between thrombosis and blood tests and, therefore, their interpretation is questionable. Recently, sensitive and specific assays have been developed for the detection of products of intravascular thrombin formation, of plasmin digests of fibrin or fibrinogen and of platelet specific proteins that are released into the plasma when platelets react with stimuli. Blood abnormalities have been sought that can either predict or detect venous thrombosis. Many of the predictive tests evaluated are nonspecific acute phase reactant responses to inflammation; of these, only reduced fibrinolytic activity has been consistently reported to be associated with postoperative venous thrombosis. Hereditary antithrombin III deficiency has been consistently shown to predispose patients to venous thrombosis. Abnormalities of the plasminogen and fibrinogen molecule have also been described in patients with familial or recurrent venous thrombosis but these are rare and the association could be coincidental. Two blood tests, the fibrinopeptide A assay and the assay for fibrin/fibrinogen fragment E are highly sensitive to acute venous thromboembolism in symptomatic patients but both are nonspecific. Elevated levels of beta thromboglobulin and platelet factor 4 have been reported in patients with arterial thromboembolism but the sensitivity and specificity of these findings is presently unknown. Topics: Antithrombin III; Arteries; Blood Coagulation Tests; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinopeptide A; Humans; Inflammation; Platelet Adhesiveness; Platelet Aggregation; Risk; Thrombin; Thromboembolism; Thrombophlebitis; Thrombosis; Wounds and Injuries | 1981 |
[Initiation in vivo of blood coagulation. The role of white blood cells and tissue factor (author's transl)].
Tissue factor is an ubiquitous phospholipid-protein complex, which triggers blood coagulation through the so-called extrinsic pathway. Reactions initiated by tissue factor bypass many of the early stages of coagulation (contact phase) and involve factors VII, X, V, II and fibrinogen but also factor IX (and VIII) as it was recently demonstrated. So, it appears that tissue factor has a key-role in the haemostasic process as it has been suggested by the mildness or the absence of haemorrhagic syndrome in contact factors deficiencies. Tissue factor activity has been found in many types of cells, especially in white bloods cells. Experimental studies have demonstrated the presence of tissue factor activity in polymorphonuclears, lymphocytes, monocytes (or macrophages). This activity is enhanced by gram-negative endotoxin stimulation, inflammation, cell mediated immunologic phenomena or malignancy. These data are in good agreement with a wild range of features observed in human pathology: fibrin deposits in inflammatory lesions, disseminated intravascular coagulation (DIC) during the course of gram-negative septicemias or acute promyelocytic leukemias, local thrombi at the early phase of graft rejection. The protective effect of a phospholipase C against DIC induced in rats by tissue factor infusion suggests in the future, a specific therapy would be possible in man that, in the frequent clinical conditions involving clotting activation through tissue factor pathway. Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Fibrin; Graft Rejection; Humans; Inflammation; Leukemia; Leukocytes; Rabbits; Sepsis; Thromboplastin | 1979 |
Mediating systems in inflammatory disease.
This article reviews the mediation systems participating or potentially participating in inflammatory disease, especially in immunologic injury of the glomerulus. Mediator systems are separated into 3 mechanisms: the first involves complement and neutrophils; the second involves systems unrelated to neutrophils and complement components from C3 to C9; and the third involves blood monocytes. Major emphasis is given to an analysis of factors that potentially participate in the second mechanism. These include humoral factors such as the coagulation system and Hageman factor systems and cellular factor such as platelets or cells resident in the glomerulus. Studies on a role of vasoactive amines are presented. The importance of separating neutrophil-dependent and -independent mechanisms in these studies is emphasized. A review of current knowledge of the biochemical mechanisms involved in the Hageman factor system is presented because of the potential role of these components in the development of inflammation. Topics: Animals; Basement Membrane; Complement System Proteins; Factor XII; Fibrin; Fibrinogen; Glomerulonephritis; Immune Complex Diseases; Inflammation; Intrinsic Factor; Kidney Glomerulus; Nephritis; Rabbits; Rats | 1978 |
Dowling oration 1975. Fibrinolysis and vasculitis.
Topics: Administration, Topical; Adolescent; Adult; Aged; Anabolic Agents; Animals; Child; Child, Preschool; Chronic Disease; Endothelium; Ethylestrenol; Female; Fibrin; Fibrinolysin; Fibrinolysis; Follow-Up Studies; Histocytochemistry; Humans; Inflammation; Leg Ulcer; Male; Middle Aged; Phenformin; Purpura; Rats; Skin Diseases; Thrombophlebitis; Vascular Diseases; Wound Healing | 1976 |
Fibrinolysis.
Topics: Aminocaproates; Anabolic Agents; Androgens; Antifibrinolytic Agents; Arterial Occlusive Diseases; Blood Platelets; Clofibrate; Drug Combinations; Ethylestrenol; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Inflammation; Insulin; Methods; Phenformin; Plasminogen; Sulfonylurea Compounds | 1973 |
Participation of components of the blood coagulation system in the inflammatory response.
Topics: Arthritis; Blood Coagulation Factors; Blood Platelets; Chronic Disease; Complement System Proteins; Connective Tissue; Disseminated Intravascular Coagulation; Endotoxins; Factor XII; Fibrin; Fibrinogen; Fibrinolysin; Glomerulonephritis; Humans; Inflammation; Kinins; Leukocytes; Nephritis; Shwartzman Phenomenon | 1972 |
Lysosomal enzymes and inflammation with particular reference to rheumatoid diseases.
Topics: Animals; Antigens; Arthritis, Rheumatoid; Autoimmune Diseases; Cartilage; Cattle; Cell Membrane Permeability; Densitometry; Esterases; Fibrin; Fibrinolysis; Histocytochemistry; Humans; Hyaluronoglucosaminidase; Hydrocortisone; Inflammation; Kinins; Leukocytes; Lysosomes; Mice; Microscopy, Electron; Neuraminidase; Oxidation-Reduction; Peptide Hydrolases; Phagocytosis; Phosphoric Monoester Hydrolases; Pinocytosis; Proteins; Rabbits; Rats; Rheumatic Diseases; Synovial Membrane; Synovitis | 1971 |
Blood coagulation and related plasma enzymes in inflammation.
Topics: Angioedema; Blood Coagulation; Blood Platelets; Capillary Permeability; Chemotaxis; Complement System Proteins; Factor XI; Fibrin; Fibrinolysis; Humans; Hypotension; Inflammation; Kallikreins; Kinins; Peptide Hydrolases; Peptides; Platelet Adhesiveness; Thrombin; Toxins, Biological | 1970 |
On the mechanism of thrombosis.
Topics: Adenine Nucleotides; Blood Coagulation; Blood Flow Velocity; Blood Platelets; Blood Vessels; Factor X; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Inflammation; Lipid Metabolism; Liver; Prothrombin; Thrombin; Thrombosis | 1969 |
Trials
6 trial(s) available for fibrin and Inflammation
Article | Year |
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Intraperitoneal heparin ameliorates the systemic inflammatory response in PD patients.
Patients with end-stage renal disease (ESRD) suffer from high mortality rates of cardiovascular diseases, conditions closely linked to the magnitude of their chronic low-grade inflammation. As heparins have been suggested to possess anti-inflammatory properties, we set out to investigate the impact of long-term treatment with intraperitoneal heparin on local and systemic inflammation in peritoneal dialysis (PD) patients.. In a double-blinded cross-over study, 21 PD patients with ESRD were randomised to inject either 4,500 anti-Xa IU tinzaparin or placebo (isotonic saline) into their morning dialysis bags every day for two periods of 3 months separated by a 1-month wash-out period. Blood and dialysate samples were analysed for inflammatory markers at the start and end of each treatment period. In dialysate, the appearance rates of the inflammatory markers were calculated to adjust for ultrafiltration variations.. Eleven patients completed the trial. Treatment with intraperitoneal tinzaparin was accompanied with a median 25.8% reduction of the plasma C-reactive protein concentration (p = 0.032), a 7.3% reduction of the plasma fibrinogen concentration (p = 0.042) and a 54.5% reduction of the dialysate interleukin 6 appearance rate (p = 0.007) compared with placebo.. Long-term treatment with intraperitoneal tinzaparin of ESRD patients on PD reduces local and systemic concentrations of inflammatory markers. Topics: Adult; Aged; C-Reactive Protein; Cross-Over Studies; Double-Blind Method; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Heparin, Low-Molecular-Weight; Humans; Inflammation; Injections, Intraperitoneal; Kidney Failure, Chronic; Male; Middle Aged; Tinzaparin | 2005 |
No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults.
Elevated homocysteine levels are associated with an increased cardiovascular disease (CVD) risk, but the underlying mechanism is still unclear. High homocysteine might affect the endothelium, and consequently lead to impaired haemostasis. In a randomized placebo controlled trial among 276 older adults with plasma total homocysteine concentrations above 13 mM at screening, we investigated the effect of homocysteine lowering by folic acid supplementation (0.8 mg/day) for 1 year on markers of endothelial function (von Willebrand factor), coagulation (tissue factor, factor VIIa, fragments 1+2), and fibrinolysis (fibrin degradation products, tissue-type plasminogen activator), and inflammation (C-reactive protein). Despite a 24% reduction in plasma homocysteine concentration and four-fold increase in serum folate concentration in the folic acid group compared to the placebo group, there was no clear change in any of the haemostasis markers, nor CRP. Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by one-year folic acid supplementation does not influence haemostasis markers. Topics: Aged; C-Reactive Protein; Cardiovascular Diseases; Dietary Supplements; Factor VIIa; Female; Fibrin; Folic Acid; Hemostasis; Homocysteine; Humans; Inflammation; Male; Middle Aged; Placebos; Risk; Thromboplastin; Time Factors; von Willebrand Factor | 2005 |
Activation of the inflammation, coagulation, and fibrinolysis systems, without influence of abciximab infusion in patients with non-ST-elevation acute coronary syndromes treated with dalteparin: a GUSTO IV substudy.
In acute coronary syndromes, the inflammation and the coagulation systems are activated, implying an impaired outcome. In addition to platelet inhibition, recent evidence suggests that the glycoprotein IIb/IIIa receptor inhibitor abciximab attenuates inflammation and coagulation activity.. The Swedish Global Utilization of Strategies To open Occluded arteries-IV (GUSTO-IV) substudy included 404 patients with non-ST-elevation acute coronary syndromes. In addition to aspirin and dalteparin, all patients were randomized to receive abciximab infusion for 24 hours or 48 hours or corresponding placebo without early coronary revascularization. Plasma samples were obtained at baseline and 24, 48, and 72 hours.. The median levels of the coagulation markers thrombin/antithrombin complex and soluble fibrin increased significantly from 3.1 to 3.7 ug/L (baseline to peak; P <.001) and from 20 to 23 nmol/L (P <.001), respectively. The fibrinolysis marker, tissue plasminogen-activator, also increased its median levels, from 11.7 to 17.5 ug/L (P <.001), whereas the median level of plasminogen-activator-inhibitor was unchanged. The inflammatory markers interleukin-6, C-reactive protein, and fibrinogen also increased their median levels (5.4-7.8 ng/L, P <.001; 4.4-8.7 mg/L, P <.001; 3.3-3.9 g/L, P <.001). However, there were no differences in median levels or in changes of median levels of any marker at any point between the placebo group and any of the abciximab groups.. In non-ST-elevation acute coronary syndrome, there was a simultaneous activation of the inflammation, coagulation, and fibrinolysis systems, despite aspirin and dalteparin treatment. Prolonged treatment with abciximab had no influence of the activation of these systems. Topics: Abciximab; Aged; Angina, Unstable; Antibodies, Monoclonal; Anticoagulants; Biomarkers; Blood Coagulation; Blood Coagulation Factors; C-Reactive Protein; Dalteparin; Double-Blind Method; Electrocardiography; Female; Fibrin; Fibrinolysis; Humans; Immunoglobulin Fab Fragments; Inflammation; Interleukin-6; Male; Middle Aged; Platelet Aggregation Inhibitors | 2004 |
Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569].
PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care).. Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism.. Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin-antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days.. Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups. Topics: APACHE; Biomarkers; Blood Coagulation Disorders; C-Reactive Protein; Disseminated Intravascular Coagulation; Endothelium; Fibrin; Fibrinolysis; Humans; Inflammation; Partial Thromboplastin Time; Placebos; Prognosis; Protein C; Recombinant Proteins; Sensitivity and Specificity; Sepsis; Severity of Illness Index; Surgical Procedures, Operative; Surgical Wound Infection | 2004 |
[Treatment of anterior segment fibrinous reactions and hemorrhage with intracameral low dose rt-PA: clinical study and review of the literature].
to evaluate the efficacy and the safety of low dose intraocular tissue plasminogen activator (rt-PA) in the treatment of traumatic hyphema and postoperative fibrinous membrane.. Six microg to 10 microg of rt-PA was injected into the anterior chamber to treat severe fibrinous postoperative membranes and total traumatic hyphemae.. Thirteen eyes of 13 patients were treated. Four cases of traumatic hyphema and 9 cases of fibrinous membranes were included. Complete fibrinolysis within 24 hours was observed in 4 cases (30.8%). A partial success was noted in 7 eyes (53.8%). No beneficial effect was observed in two cases of traumatic hyphema associated with intravitreal hemorrhage after penetrating trauma. No side effect attributable to rt-PA occurred.. Low dose intraocular rt-PA appears to be safe and effective in the treatment of postoperative fibrinous membrane and endocular hemorrhage limited to the anterior chamber. Topics: Adolescent; Adult; Aged; Child; Eye Injuries; Female; Fibrin; Fibrinolytic Agents; Humans; Hyphema; Inflammation; Male; Middle Aged; Ophthalmologic Surgical Procedures; Postoperative Complications; Recombinant Proteins; Tissue Plasminogen Activator | 2000 |
Carbon dioxide laser for de-epithelialization of periodontal flaps.
Regeneration of mineralized and soft connective tissue components of the attachment apparatus is the main goal in the treatment of periodontal diseases. Often, apical migration of epithelium (long junctional epithelium) effectively prevents the formation of bone and connective tissue attachment after periodontal surgery. The purpose of the present study was to compare conventional periodontal surgery combined with carbon dioxide laser and conventional periodontal surgery alone with respect to epithelial elimination and degree of necrosis of mucoperiosteal flaps. After signing a consent form, five patients with at least two comparable bilateral periodontal defects needing pocket elimination surgery participated in this study. The investigators randomly divided each side into test and control sites. Each patient received oral hygiene instruction and initial therapy prior to surgery. At surgery, the test site received a sulcular incision and carbon dioxide laser de-epithelialization of the outer and inner aspects of the flap. The control group received reverse bevel incision only. The surgeon performed open flap debridement on all teeth. At the time of surgery, the surgeon did a biopsy of each site and submitted specimens for histologic evaluation. A matched pairs t-test was used to analyze the data. The results show significant differences between the carbon dioxide laser and reverse bevel incision with respect to sulcular (P < or = 0.025) and gingival (external) (P < or = 0.01) flap surface epithelial elimination and tissue necrosis (P < or = 0.005). These results should be replicated with a larger number of subjects. The carbon dioxide laser eliminated sulcular and gingival (external) epithelium without disturbing underlying connective tissue. This finding supports the concept that the carbon dioxide wavelength has little or no effect on tissues beyond the target. However, neither laser nor blade eliminated all the epithelium. Researchers observed chronic inflammation in the control and test sites, with a predominance of plasma cells. Lining the sulcular and gingival (external) lased areas, investigators found coagulation necrosis covered by fibrin and coagulated blood. The laser appears to effectively remove epithelium at the time of surgery; however, future long-term, well-controlled quantitative histologic studies are needed to evaluate the effect of repeated carbon dioxide laser de-epithelialization of the gingival (external) surface of mucoperiosteal Topics: Biopsy; Blood Coagulation; Carbon Dioxide; Cell Movement; Connective Tissue; Debridement; Epithelial Attachment; Epithelium; Female; Fibrin; Gingivectomy; Humans; Inflammation; Laser Therapy; Male; Matched-Pair Analysis; Necrosis; Oral Hygiene; Periodontal Diseases; Periodontal Pocket; Periodontium; Plasma Cells; Regeneration; Surgical Flaps; Wound Healing | 1997 |
Other Studies
274 other study(ies) available for fibrin and Inflammation
Article | Year |
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A novel interaction between extracellular vimentin and fibrinogen in fibrin formation.
Thrombosis is frequently manifested in critically ill patients with systemic inflammation, including sepsis and COVID-19. The coagulopathy in systemic inflammation is often associated with increased levels of fibrinogen and D-dimer. Because elevated levels of vimentin have been detected in sepsis, we sought to investigate the relationship between vimentin and the increased fibrin formation potential observed in these patients.. This hypothesis was examined by using recombinant human vimentin, anti-vimentin antibodies, plasma derived from healthy and critically ill patients, confocal microscopy, co-immunoprecipitation assays, and size exclusion chromatography.. The level of vimentin in plasma derived from critically ill subjects with systemic inflammation was on average two-fold higher than that of healthy volunteers. We determined that vimentin directly interacts with fibrinogen and enhances fibrin formation. Anti-vimentin antibody effectively blocked fibrin formation ex vivo and caused changes in the fibrin structure in plasma. Additionally, confocal imaging demonstrated plasma vimentin enmeshed in the fibrin fibrils. Size exclusion chromatography column and co-immunoprecipitation assays demonstrated a direct interaction between extracellular vimentin and fibrinogen in plasma from critically ill patients but not in healthy plasma.. The results describe that extracellular vimentin engages fibrinogen in fibrin formation. In addition, the data suggest that elevated levels of an apparent aberrant extracellular vimentin potentiate fibrin clot formation in critically ill patients with systemic inflammation; consistent with the notion that plasma vimentin contributes to the pathogenesis of thrombosis. Topics: COVID-19; Critical Illness; Extracellular Space; Fibrin; Fibrinogen; Hemostatics; Humans; Inflammation; Thrombosis; Vimentin | 2023 |
Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation.
Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage. Topics: Animals; Extracellular Traps; Fibrin; Fibrinolysin; Inflammation; Interleukin-6; Mice; Plasminogen; Sepsis | 2023 |
Composite Fibrin and Carbon Microfibre Implant to Modulate Postraumatic Inflammation after Spinal Cord Injury.
Poor functional recovery after spinal cord injury (SCI) drives the development of novel strategies to manage this devastating condition. We recently showed promising immunomodulatory and pro-regenerative actions of bio-functionalized carbon microfibres (MFs) implanted in a rodent model of SCI. In order to maximize tissue repair while easing MF implantation, we produced a composite implant based on the embedding of several MFs within a fibrin hydrogel. We used intravital imaging of fluorescent reporter mice at the early stages and spinal sections of the same animals 3 months later to characterize the neuroinflammatory response to the implant and its impact on axonal regeneration. Whereas fibrin alone was inert in the first week, its enzymatic degradation drove the chronic activation of microglial cells and axonal degeneration within 3 months. However, the presence of MFs inside the fibrin hydrogel slowed down fibrin degradation and boosted the early recruitment of immune cells. Noteworthy, there was an enhanced contribution of monocyte-derived dendritic cells (moDCs), preceding a faster transition toward an anti-inflammatory environment with increased axonal regeneration over 3 months. The inclusion of MF here ensured the long-term biocompatibility of fibrin hydrogels, which would otherwise preclude successful spinal cord regeneration. Topics: Animals; Fibrin; Hydrogels; Inflammation; Mice; Spinal Cord Injuries; Spinal Cord Regeneration | 2023 |
Morphological prediction of lethal outcomes in the evaluation of lung tissue structural changes in patients on respiratory support with СOVID-19: Ukrainian experience.
The impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on lung tissue in patients on respiratory support is of significant scientific interest in predicting mortality. This study aimed to analyze post-mortem histological changes in the lung tissue of COVID-19 patients on respiratory support using vital radiology semiotics. A total of 41 autopsies were performed on patients who died of SARS-CoV-2 and had confirmed COVID-19 by polymerase chain reaction (PCR) and radiological evidence of lung tissue consolidation and ground glass opacity. The results showed that the duration of COVID-19 in patients on respiratory support was significantly associated with the development of all stages of diffuse alveolar damage, acute fibrous organizing pneumonia, pulmonary capillary congestion, fibrin thrombi, perivascular inflammation, alveolar hemorrhage, proliferating interstitial fibroblasts, and pulmonary embolism. The prediction model for lethal outcomes based on the duration of total respiratory support had a sensitivity of 68.3% and a specificity of 87.5%. In conclusion, for COVID-19 patients on long-term respiratory support with radiological signs of ground glass opacity and lung consolidation, post-mortem morphological features included various stages of diffuse alveolar lung damage, pulmonary capillary congestion, fibrin clots, and perivascular inflammation. Topics: COVID-19; Fibrin; Humans; Inflammation; Lung; SARS-CoV-2; Thrombosis | 2023 |
A 3-
Dysregulated inflammation and coagulation are underlying mechanisms driving organ injury after trauma and hemorrhagic shock. Heparan sulfates, cell surface glycosaminoglycans abundantly expressed on the endothelial surface, regulate a variety of cellular processes. Endothelial heparan sulfate containing a rare 3-. Male Sprague-Dawley rats were pre-treated subcutaneously with vehicle (saline) or dekaparin (2 mg/kg) and subjected to a trauma/hemorrhagic shock model through laparotomy, gut distention, and fixed-pressure hemorrhage. Vehicle and dekaparin-treated rats were resuscitated with Lactated Ringer's solution (LR) and compared to vehicle-treated fresh-frozen-plasma-(FFP)-resuscitated rats. Serial blood samples were collected at baseline, after induction of shock, and 3 hours after fluid resuscitation to measure hemodynamic and metabolic shock indicators, inflammatory mediators, and thrombin-antithrombin complex formation. Lungs and kidneys were processed for organ injury scoring and immunohistochemical analysis to quantify presence of neutrophils.. Induction of trauma and hemorrhagic shock resulted in significant increases in thrombin-antithrombin complex, inflammatory markers, and lung and kidney injury scores. Compared to vehicle, dekaparin treatment did not affect induction, severity, or recovery of shock as indicated by hemodynamics, metabolic indicators of shock (lactate and base excess), or metrics of bleeding, including overall blood loss, resuscitation volume, or hematocrit. While LR-vehicle-resuscitated rodents exhibited increased lung and kidney injury, administration of dekaparin significantly reduced organ injury scores and was similar to organ protection conferred by FFP resuscitation. This was associated with a significant reduction in neutrophil infiltration in lungs and kidneys and reduced lung fibrin deposition among dekaparin-treated rats compared to vehicle. No differences in organ injury, neutrophil infiltrates, or fibrin staining between dekaparin and FFP groups were observed. Finally, dekaparin treatment attenuated induction of thrombin-antithrombin complex and inflammatory mediators in plasma following trauma and hemorrhagic shock.. Anti-thromboinflammatory properties of a synthetic 3- Topics: Animals; Fibrin; Heparitin Sulfate; Inflammation; Male; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Sulfates; Thromboinflammation; Thrombosis | 2023 |
Macrophages-derived Factor XIII links coagulation to inflammation in COPD.
The local, extravascular, activation of the coagulation system in response to injury is a key factor mediating the resulting inflammatory response. Coagulation Factor XIIIA (FXIIIA) found in alveolar macrophages (AM) and dendritic cells (DC), by influencing fibrin stability, might be an inflammatory modifier in COPD.. To study the expression of FXIIIA in AM and Langerin+DC (DC-1) and their relation to the inflammatory response and disease progression in COPD.. In 47 surgical lungs, 36 from smokers (22 COPD and 14 no-COPD) and 11 from non-smokers we quantified by immunohistochemistry FXIIIA expression in AM and DC-1 along with numbers of CD8+Tcells and CXCR3 expression in lung parenchyma and airways. Lung function was measured prior to surgery.. The percentage of AM expressing FXIII (%FXIII+AM) was higher in COPD than no-COPD and non-smokers. DC-1 expressed FXIIIA and their numbers were higher in COPD than no-COPD and non-smokers. DC-1 positively correlated with %FXIII+AM (r=0.43; p<0.018). CD8+Tcells, which were higher in COPD than in no-COPD, were correlated with DC-1 (p<0.01) and %FXIII+AM. CXCR3+ cells were increased in COPD and correlated with %FXIII+AM (p<0.05). Both %FXIII+AM (r=-0.6; p=0.001) and DC-1 (r=-0.7; p=0.001) correlated inversely with FEV. FXIIIA, an important link between the extravascular coagulation cascade and inflammatory response, is significantly expressed in alveolar macrophages and dendritic cells of smokers with COPD, suggesting that it could play an important role in the adaptive inflammatory reaction characteristic of the disease. Topics: Factor XIII; Factor XIIIa; Fibrin; Humans; Inflammation; Macrophages | 2023 |
Plasma fibrin membranes loaded with bone marrow mesenchymal stem cells and corneal epithelial cells promote corneal injury healing
The shortage of corneal donors has prompted the development of tissue-engineered corneal grafts as an alternative solution. Currently, amniotic membranes with good biocompatibility are widely used as scaffolds for loading stem cells in the treatment of corneal injury. However, this approach has its limitations. In this study, BMSCs were induced to differentiate into corneal epithelial cells Topics: Animals; Bone Marrow Cells; Burns; Corneal Injuries; Epithelial Cells; Fibrin; Fibrosis; Inflammation; Mesenchymal Stem Cells; Rats | 2023 |
Dynamic intravital imaging reveals reactive vessel-associated microglia play a protective role in cerebral malaria coagulopathy.
Vascular congestion and coagulopathy have been shown to play a role in human and experimental cerebral malaria (eCM), but little is known about the role of microglia, or microglia-vascular interactions and hypercoagulation during disease progression in this fatal infection. Recent studies show microglia bind to fibrinogen, a glycoprotein involved in thrombosis. An eCM model of Plasmodium chabaudi infection in mice deficient in the regulatory cytokine IL-10 manifests neuropathology, including hypercoagulation with extensive fibrin(ogen) deposition and neuroinflammation. Intravital microscopy and immunofluorescence are applied to elucidate the role of microglia in eCM. Results show microgliosis and coagulopathy occur early in disease at 3 dpi (day post-infection), and both are exacerbated as disease progresses to 7dpi. Vessel associated microglia increase significantly at 7 dpi, and the expression of the microglial chemoattractant CCL5 (RANTES) is increased versus uninfected and localized with fibrin(ogen) in vessels. PLX3397 microglia depletion resulted in rapid behavioral decline, severe hypothermia, and greater increase in vascular coagulopathy. This study suggests that microglia play a prominent role in controlling infection-initiated coagulopathy and supports a model in which microglia play a protective role in cerebral malaria by migrating to and patrolling the cerebral vasculature, potentially regulating degree of coagulation during systemic inflammation. Topics: Animals; Cytokines; Disease Models, Animal; Fibrin; Humans; Inflammation; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Microglia | 2023 |
Mesopore Controls the Responses of Blood Clot-Immune Complex via Modulating Fibrin Network.
Formation of blood clots, particularly the fibrin network and fibrin network-mediated early inflammatory responses, plays a critical role in determining the eventual tissue repair or regeneration following an injury. Owing to the potential role of fibrin network in mediating clot-immune responses, it is of great importance to determine whether clot-immune responses can be regulated via modulating the parameters of fibrin network. Since the diameter of D-terminal of a fibrinogen molecule is 9 nm, four different pore sizes (2, 8, 14, and 20 nm) are rationally selected to design mesoporous silica to control the fibrinogen adsorption and modulate the subsequent fibrin formation process. The fiber becomes thinner and the contact area with macrophages decreases when the pore diameters of mesoporous silica are greater than 9 nm. Importantly, these thinner fibers grown in pores with diameters larger than 9 nm inhibit the M1-polorazation of macrophages and reduce the productions of pro-inflammatory cytokines and chemokines by macrophages. These thinner fibers reduce inflammation of macrophages through a potential signaling pathway of cell adhesion-cytoskeleton assembly-inflammatory responses. Thus, the successful regulation of the clot-immune responses via tuning of the mesoporous pore sizes indicates the feasibility of developing advanced clot-immune regulatory materials. Topics: Animals; Blood Coagulation; Disease Models, Animal; Fibrin; Inflammation; Rats; Thrombosis; Wound Healing | 2022 |
Transcription Factor Specificity Protein 1 Regulates Inflammation and Fibrin Deposition in Nasal Polyps Via the Regulation of microRNA-125b and the Wnt/β-catenin Signaling Pathway.
Nasal polyps (NPs) are multifactorial soft growths inside the nasal passages and are associated with chronic inflammation that originate from the nasal and paranasal sinus mucosae. This study focused on the role of microRNA (miR)-125b and the molecules associated with NP development. Differentially expressed miRNAs between nasal tissues from patients with chronic rhinosinusitis (CRS) with NP (CRSwNP) and CRS without NP (CRSsNP) were screened using microarray analysis. A murine model of CRSwNP was established. The expression of miR-125b in murine tissues was examined using reverse transcription quantitative polymerase chain reaction. Candidate upstream regulators of miR-125b were predicted using bioinformatics tools, and the binding relationship between specificity protein 1 (Sp1) and miR-125b was validated using luciferase and chromatin immunoprecipitation assays. Altered expression of Sp1 and miR-125b was induced to evaluate their relevance to the progression of NPs. miR-125b expression was significantly upregulated in NP tissues from patients with CRSwNP. Sp1 was confirmed as an upstream regulator that promotes miR-125b transcription in NPs. Overexpression of Sp1 reduced levels of d-dimer (an indicator of fibrinogen degradation products) and tissue-type plasminogen activator (t-PA) but increased eosinophil cationic protein and peroxidase levels, as well as the levels of inflammatory factors interleukin-5 (IL-5) and IL-8 in murine NP tissues. However, these trends were reversed after miR-125b downregulation. Sp1 and miR-125b were found to activate the Wnt/β-catenin signaling pathway in NPs. This study demonstrated that Sp1, an upstream transcription factor of miR-125b, accumulates on the miR-125b promoter to activate its transcription, which induces inflammation and fibrin deposition in NP by activating the Wnt/β-catenin axis. Topics: Animals; Chronic Disease; Fibrin; Humans; Inflammation; Mice; MicroRNAs; Nasal Polyps; Rhinitis; Sinusitis; Sp1 Transcription Factor; Wnt Signaling Pathway | 2022 |
Dual functions of the fibrin βN-domains in the VLDL receptor-dependent pathway of transendothelial migration of leukocytes.
Our previous studies revealed that fibrin interacts with the VLDL receptor (VLDLR) through a pair of its βN-domains and this interaction promotes transendothelial migration of leukocytes and, thereby, inflammation. In agreement, the NDSK-II fragment representing the central part of the fibrin molecule and containing these domains stimulates leukocyte transmigration. However, the recombinant (β15-66) Topics: Endothelium, Vascular; Fibrin; Humans; Inflammation; Leukocytes; Receptors, LDL; Transendothelial and Transepithelial Migration | 2022 |
Radiotracers to Address Unmet Clinical Needs in Cardiovascular Imaging, Part 2: Inflammation, Fibrosis, Thrombosis, Calcification, and Amyloidosis Imaging.
Cardiovascular imaging is evolving in response to systemwide trends toward molecular characterization and personalized therapies. The development of new radiotracers for PET and SPECT imaging is central to addressing the numerous unmet diagnostic needs that relate to these changes. In this 2-part review, we discuss select radiotracers that may help address key unmet clinical diagnostic needs in cardiovascular medicine. Part 1 examined key technical considerations pertaining to cardiovascular radiotracer development and reviewed emerging radiotracers for perfusion and neuronal imaging. Part 2 covers radiotracers for imaging cardiovascular inflammation, thrombosis, fibrosis, calcification, and amyloidosis. These radiotracers have the potential to address several unmet needs related to the risk stratification of atheroma, detection of thrombi, and the diagnosis, characterization, and risk stratification of cardiomyopathies. In the first section, we discuss radiotracers targeting various aspects of inflammatory responses in pathologies such as myocardial infarction, myocarditis, sarcoidosis, atherosclerosis, and vasculitis. In a subsequent section, we discuss radiotracers for the detection of systemic and device-related thrombi, such as those targeting fibrin (e.g., Topics: Amyloidosis; Calcinosis; Fibrin; Fibrosis; Humans; Inflammation; Positron-Emission Tomography; Thrombosis | 2022 |
Fibrin(ogen) Is Constitutively Expressed by Differentiated Intestinal Epithelial Cells and Mediates Wound Healing.
Fibrinogen is a large molecule synthesized in the liver and released in the blood. Circulating levels of fibrinogen are upregulated after bleeding or clotting events and support wound healing. In the context of an injury, thrombin activation drives conversion of fibrinogen to fibrin. Fibrin deposition contains tissue damage, stops blood loss, and prevents microbial infection. In most circumstances, fibrin needs to be removed to allow the resolution of inflammation and tissue repair, whereas failure of this may lead to the development of various disorders. However, the contribution of fibrinogen to tissue inflammation and repair is likely to be context-dependent. In this study, the concept that fibrin needs to be removed to allow tissue repair and to reduce inflammation is challenged by our observations that, in the intestine, fibrinogen is constitutively produced by a subset of intestinal epithelial cells and deposited at the basement membrane as fibrin where it serves as a substrate for wound healing under physiological conditions such as epithelial shedding at the tip of the small intestinal villus and surface epithelium of the colon as well as under pathological conditions that require rapid epithelial repair. The functional integrity of the intestine is ensured by the constant renewal of its simple epithelium. Superficial denuding of the epithelial cell layer occurs regularly and is rapidly corrected by a process called restitution that can be influenced by various soluble and insoluble factors. Epithelial cell interaction with the extracellular matrix greatly influences the healing process by acting on cell morphology, adhesion, and migration. The functional contribution of a fibrin(ogen) matrix in the intestine was studied under physiological and pathological contexts. Our results (immunofluorescence, immunoelectron microscopy, and quantitative PCR) show that fibrin(ogen) is a novel component of the basement membrane associated with the differentiated epithelial cell population in both the small intestine and colon. Fibrin(ogen) alone is a weak ligand for epithelial cells and behaves as an anti-adhesive molecule in the presence of type I collagen. Furthermore, the presence of fibrin(ogen) significantly shortens the time required to achieve closure of wounded epithelial cell monolayers and co-cultures in a PI3K-dependent manner. In human specimens with Crohn's disease, we observed a major accumulation of fibrin(ogen) throughout the tissue and at denu Topics: Animals; Epithelial Cells; Estrone; Fibrin; Fibrinogen; Inflammation; Intestines; Mice; Phosphatidylinositol 3-Kinases; Wound Healing | 2022 |
FGL2-MCOLN3-Autophagy Axis-Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis.
Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are 2 main features of FVH. Here, we investigated the role and mechanism of NETs in the pathogenesis of FVH.. A mouse model of FVH was established by murine hepatitis virus strain-3 infection. Liver leukocytes of infected or uninfected mice were used for single-cell RNA sequencing and whole-transcriptome sequencing. NETs depletion was achieved using DNase 1. Acetaminophen was used to establish a mouse model of non-virus-caused acute liver failure. Clinically, NETs-related markers in liver, plasma, and peripheral neutrophils were assessed in patients with hepatitis B virus (HBV)-related acute liver injury.. Increased hepatic NETs formation was observed in murine hepatitis virus strain-3-infected mice, but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. An adoptive transfer experiment showed that neutrophil-specific fibrinogen-like protein 2 (FGL2) promoted NETs formation. FGL2 was found to directly interact with mucolipin 3, which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, increased plasma NETs level was associated with coagulation dysfunction in patients with HBV acute liver injury. Colocalization of FGL2, NETs, and fibrin in liver was observed in these patients.. NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2-mucolipin 3-autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH. Topics: Acetaminophen; Animals; Autophagy; Calcium; Deoxyribonucleases; Disease Models, Animal; Extracellular Traps; Fibrin; Fibrinogen; Hepatitis, Viral, Animal; Hepatitis, Viral, Human; Inflammation; Mice; Mice, Inbred BALB C; Murine hepatitis virus | 2022 |
Role of coagulation in persistent renal ischemia following reperfusion in an animal model.
Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation. Topics: Acute Kidney Injury; Animals; Creatinine; Disease Models, Animal; Fibrin; Inflammation; Ischemia; Kidney; Reperfusion; Reperfusion Injury; Thromboplastin; Urokinase-Type Plasminogen Activator | 2022 |
Neutrophil Extracellular Traps Enhance Liver Inflammation and Fibrin Deposition in Fulminant Viral Hepatitis.
Topics: Extracellular Traps; Fibrin; Hepatitis, Viral, Human; Humans; Inflammation | 2022 |
Multiple cerebral infarctions due to calcified amorphous tumor growing rapidly from an antecedent infection and decreasing rapidly by detachment of fibrin and antithrombotic drugs: a case report.
Calcified amorphous tumor (CAT) of the heart is a rare non-neoplastic intracardiac mass, a calcium deposition surrounded by amorphous fibrous tissue, and possibly causes cerebral embolism. Even rarer is CAT associated with infection, and no CAT with antecedent infection has been reported to our knowledge. In addition, although some CAT in patients on hemodialysis has been reported to grow rapidly, no case has been reported on CAT that grew and diminished rapidly in a short period of time. Here, we report the case of an 82-year-old Japanese woman with normal renal function who developed multiple cerebral infarctions due to CAT that grew rapidly, associated with inflammation from an antecedent infection, and diminished rapidly by detachment of fibrin on the mass surface and antithrombotic drugs.. The patient developed fever after dental treatment and found musical hallucination on the left ear worsened in degree and frequency. In a nearby clinic, she was treated with antibiotics, and her body temperature turned to normal in approximately 1 month. She presented to our hospital for workup on the worsened musical hallucination. Magnetic resonance imaging (MRI) showed multiple cerebral infarctions, and transthoracic echocardiography (TTE) revealed an immobile hyperechoic mass with an acoustic shadow arising from a posterior cusp of the mitral valve. CAT was suspected and treated with apixaban and aspirin. Follow-up MRI and TTE showed newly developed multiple cerebral infarctions and rapidly diminished CAT. Cardiac surgery was performed to resect the CAT. The pathological findings showed calcifications surrounded by amorphous fibrous tissue including fibrin, indicating CAT. The patient's symptoms improved and no cerebral infarctions recurred in 4 months follow-up.. Inflammation from an antecedent infection can cause CAT to grow rapidly. Fibrous tissue including fibrin may attach to the surface of CAT, resulting in multiple cerebral infarctions. Fibrous tissue may detach and disappear by antithrombotic drugs, leading to a rapid diminishment of CAT in size. Topics: Anti-Bacterial Agents; Aspirin; Calcinosis; Calcium; Cerebral Infarction; Female; Fibrin; Fibrinolytic Agents; Hallucinations; Heart Neoplasms; Humans; Inflammation; Neoplasm Recurrence, Local | 2022 |
LBO-EMSC Hydrogel Serves a Dual Function in Spinal Cord Injury Restoration
It is critical to obtain an anti-inflammatory microenvironment when curing spinal cord injury (SCI). On the basis of this, we prepared Topics: Animals; Axons; Cell Line; Fibrin; Humans; Hydrogels; Inflammation; Lycium; Male; Mesenchymal Stem Cells; Microglia; Nasal Mucosa; Phosphatidylinositol 3-Kinases; Polysaccharides; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor, Type II; Recovery of Function; Remyelination; Signal Transduction; Spinal Cord Injuries; Tissue Scaffolds; TOR Serine-Threonine Kinases | 2021 |
Fibrin sparks inflammation in the oral mucosa.
Fibrin deposits in the oral mucosa trigger neutrophil activation and bone destruction. Topics: Fibrin; Humans; Inflammation; Mouth Mucosa | 2021 |
Anti-coagulation for COVID-19 treatment: both anti-thrombotic and anti-inflammatory?
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications. Topics: Blood Coagulation; Cells, Cultured; Chemokines; COVID-19; COVID-19 Drug Treatment; COVID-19 Serotherapy; Cytokine Release Syndrome; Dose-Response Relationship, Drug; Fibrin; Fibrinolytic Agents; Heparin; Humans; Immunization, Passive; Inflammation; Leukocytes, Mononuclear; SARS-CoV-2 | 2021 |
EBV positive fibrin/chronic inflammation associated diffuse large B-cell lymphoma: an incidental finding associated with a breast implant.
Topics: Breast Implants; Epstein-Barr Virus Infections; Fibrin; Herpesvirus 4, Human; Humans; Incidental Findings; Inflammation; Lymphoma, Large B-Cell, Diffuse | 2021 |
Endothelial Dysfunction in the Brain: Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19.
The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19. Topics: Angiotensin-Converting Enzyme 2; Blood Coagulation; Brain; Brain Ischemia; COVID-19; Cytokines; Endothelial Cells; Fibrin; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Hypoxia; Incidence; Inflammation; Ischemic Stroke; Myocardial Infarction; Pandemics; Prognosis | 2021 |
Psoriatic disease is associated with systemic inflammation, endothelial activation, and altered haemostatic function.
Psoriasis is a chronic, immune-mediated inflammatory skin disease, affecting approximately 2% of the general population, which can be accompanied by psoriatic arthritis (PsA). The condition has been associated with an increased cardiovascular burden. Hypercoagulability is a potential underlying mechanism that may contribute to the increased risk of major cardiovascular events in psoriatic individuals. Whole blood samples were collected from 20 PsA patients and 20 healthy individuals. The concentrations of inflammatory molecules (C-reactive protein, serum amyloid A, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble P-selectin) were determined by enzyme-linked immunosorbent assays. In addition, clotting efficiency was evaluated by thromboelastography. The fibrin network architecture was also assessed by scanning electron microscopy. Elevated levels of circulating inflammatory molecules were significantly associated with the presence of psoriatic disease. Furthermore, an increased tendency towards thrombus formation was significantly predictive of disease presence. Scanning electron microscopy revealed that fibrin clots were denser in psoriatic individuals, compared to healthy controls, with an increased fibrin fibre diameter associated with psoriatic disease. Our results add to the accumulating evidence of the systemic nature of psoriasis and the subsequent risk of cardiovascular comorbidities, potentially due to an acquired hypercoagulability. We suggest that haemostatic function should be monitored carefully in psoriatic patients that present with severe disease, due to the pre-eminent risk of developing thrombotic complications. Topics: Arthritis, Psoriatic; Case-Control Studies; Endothelial Cells; Female; Fibrin; Hemostatics; Humans; Inflammation; Logistic Models; Male; Middle Aged; Psoriasis; Thrombelastography | 2021 |
Molecular Magnetic Resonance Imaging of Fibrin Deposition in the Liver as an Indicator of Tissue Injury and Inflammation.
Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation.. Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation.. After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis.. EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis. Topics: Animals; Disease Models, Animal; Fibrin; Gadolinium; Inflammation; Liver; Liver Cirrhosis; Magnetic Resonance Imaging; Male; Peptides; Rats; Rats, Wistar | 2020 |
Micro-CT and histopathology methods to assess host response of aneurysms treated with shape memory polymer foam-coated coils versus bare metal coil occlusion devices.
Recent studies utilizing shape memory polymer foams to coat embolizing coils have shown potential benefits over current aneurysm treatments. In the current study utilizing a rabbit-elastase aneurysm model, the performance of test article (foam-coated coil [FCC]) and control (bare platinum coils [BPCs]) devices were compared at 30, 90, and 180 days using micro-CT and histological assessments. The host response was measured by identifying the cells regionally present within the aneurysm, and assessing the degree of residual debris and connective tissue. The 3D reconstructions of aneurysms provided context for histologic findings, and aided in the overall aneurysm assessment. At all time points, >75% of the cells categorized in each aneurysm were associated with a bioactive yet biocompatible host response (vs. the remainder of cells that were associated with acute inflammation). The extracellular matrix exhibited a transition from residual fibrin at 30 days to a greater degree of connective tissue at 90 and 180 days. Although the control BPC-treated aneurysms exhibited a greater degree of connective tissue at the earliest time point examined (30 days), by 180 days, the FCC-treated aneurysms had more connective tissue and less debris overall than the control aneurysms. When considering cell types and extracellular matrix composition, the overall host response scores were significantly better in FCC-treated aneurysms at the later time point. Based on the results of these metrics, the FCC device may lead to an advanced tissue remodeling response over BPC occlusion devices. Topics: Animals; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Fibrin; Foreign-Body Reaction; Humans; Inflammation; Intracranial Aneurysm; Pancreatic Elastase; Platinum; Prosthesis Design; Rabbits; Risk Assessment; Smart Materials; Time Factors; Treatment Outcome; X-Ray Microtomography | 2020 |
Autologous platelet-rich fibrin stimulates canine periodontal regeneration.
Platelet-rich fibrin (PRF) provides a scaffold for cell migration and growth factors for promoting wound healing and tissue regeneration. Here, we report using PRF in periodontal healing after open flap debridement (OFD) in canine periodontitis. A split-mouth design was performed in twenty dogs. Forty periodontitis surgical sites were randomly categorized into 2 groups; OFD alone and OFD with PRF treatment. Clinical parameters of periodontal pocket depth, gingival index, and the cemento-enamel junction-alveolar bone levels/root length ratio were improved in the OFD + PRF group. The OFD + PRF group also demonstrated a dramatically decreased inflammatory score compared with the OFD group. Collagen accumulation was improved in the OFD + PRF group at later time points compared with baseline. PRF application also significantly reduced inflammatory cytokine expression (TNFA and IL1B), and promoted the expression of collagen production-related genes (COL1A1, COL3A1, and TIMP1) and growth factors (PDGFB, TGFB1, and VEGFA). These findings suggest that PRF combined with OFD provides a new strategy to enhance the overall improvement of canine periodontitis treatment outcomes, especially in terms of inflammation and soft tissue healing. Therefore, PRF use in treating periodontitis could play an important role as a regenerative material to improve canine periodontitis treatment. Topics: Alveolar Bone Loss; Animals; Chronic Periodontitis; Cytokines; Debridement; Dogs; Fibrin; Genes, Regulator; Inflammation; Intercellular Signaling Peptides and Proteins; Periodontal Index; Periodontal Pocket; Platelet-Rich Fibrin; Regeneration; Surgical Flaps; Treatment Outcome; Wound Healing | 2020 |
Fibrin lysability is associated with central obesity and inflammation in women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is characterized by increased central fat mass (CFM), hyper-inflammation, and hemostatic alterations; the risk of cardiovascular disease may also be increased. Reduced fibrin lysability is a risk factor for cardiovascular disease. The present study assessed fibrin lysability in women with PCOS and controls of similar age and body mass index.. Ninety women with PCOS and 35 controls of comparable age and body mass index were included. Hemostatic markers (fibrin lysability, fibrinogen, coagulation factor XIII, plasminogen, plasminogen activator inhibitor 1 [PAI-1], plasmin inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI), D-dimer), C-reactive protein (CRP), body mass index, waist-to-hip ratio, CFM determined by Dual-energy X-ray absorptiometry scan, and sex hormones (testosterone estradiol, and sex hormone binding globulin) were determined.. TAFI and CRP were higher in women with PCOS, than controls. In women with PCOS, fibrin lysability correlated with CFM, waist-to-hip ratio, CRP, fibrinogen, and all hemostatic variables (P ≤ .004) except TAFI and D-dimer. CFM correlated with fibrinogen, CRP, coagulation factor XIII, waist-to-hip ratio, plasminogen, PAI-1, plasmin inhibitor, and TAFI (P < .02). In controls, fibrin lysability correlated with CFM, fibrinogen, coagulation factor XIII, and plasmin inhibitor (P ≤ .02). CFM correlated with PAI-1, plasmin inhibitor, coagulation factor XIII, fibrinogen, and CRP (P ≤ .05). Stepwise regression analysis revealed that fibrin lysability was associated with CFM, fibrinogen and CRP in women with PCOS (r. Fibrin lysability was comparable in women with PCOS and controls. Fibrin lysability was associated with CFM and hyper-inflammation in women with PCOS, but only with CFM in controls. These findings suggest that obese women with PCOS and augmented inflammation could have an increased risk of cardiovascular disease. Topics: Absorptiometry, Photon; Adolescent; Adult; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Female; Fibrin; Gonadal Steroid Hormones; Humans; Inflammation; Obesity, Abdominal; Polycystic Ovary Syndrome; Risk Factors | 2020 |
Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes.
Topics: Blood Coagulation; Down-Regulation; Edema; Eosinophilia; Fibrin; Humans; Inflammation; Nasal Polyps; Tissue Plasminogen Activator | 2020 |
Atorvastatin Reduces
Arteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins' induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the. We randomized 108 C57Bl/6J mice to receive daily atorvastatin 1.14 mg/kg or PBS (control) starting 7 days before end-to-side carotid artery-jugular vein fistula creation and for up to 42 days after fistula creation. We then assessed longitudinally the effects of statin therapy on primary murine fistula patency and maturation. We concomitantly analyzed the. These findings provide new Topics: Animals; Arteriovenous Shunt, Surgical; Atorvastatin; Carotid Artery, Internal; Collagen; Female; Fibrin; Fibrosis; Hemorheology; Inflammation; Jugular Veins; Macrophages; Male; Mice; Mice, Inbred C57BL; Molecular Imaging; Nanoparticles; Random Allocation; RNA, Messenger; Thrombosis; Transcription, Genetic; Vascular Access Devices; Vascular Patency | 2020 |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation.
Systemic inflammation can lead to coagulopathy and disseminated intravascular coagulation (DIC). In prior studies, the recombinant A2 domain of human von Willebrand factor (VWF; A2 protein) attenuated DIC and decreased mortality in lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2 protein moderates DIC. We used confocal microscopy to analyze the fibrin clot structure in plasma from healthy humans and endotoxemic mice, turbidity assays to examine fibrin polymerization, and a murine model for LPS-induced DIC and introduced a loss-of-function mutation into the A2 protein for fibrin. The mutation of the residue E1567 located in the α2 helix of the folded A2 domain of VWF inhibited binding activity for fibrin, possibly mapping a novel region containing a putative binding site for fibrin. The A2 protein increased the initial rate of change of fibrin polymerization, intercalated into the fibrin network, and modified the resultant clot structure in vitro. Furthermore, ex vivo experiments using plasma from mice with endotoxemia treated with the A2 protein revealed an increased rate of fibrin formation and an altered clot structure as compared with plasma from nontreated sick animals. Moreover, and in contrast to the A2 mutant, the A2 protein improved survival and reduced fibrin deposition and microvascular thrombosis in mice with endotoxemia-induced DIC. Importantly, in vivo and in vitro studies indicated that the A2 protein did not affect experimental thrombosis. Thus, we provide evidence for a novel treatment to attenuate systemic inflammation-induced coagulopathy/DIC via targeting fibrin formation, without an increased risk for bleeding. Topics: Animals; Disseminated Intravascular Coagulation; Fibrin; Inflammation; Mice; Thrombosis; von Willebrand Factor | 2020 |
A Novel Approach for Detecting Unique Variations among Infectious Bacterial Species in Endocarditic Cardiac Valve Vegetation.
Infectious endocarditis (IE) remains one of the deadliest heart diseases with a high death rate, generally following thrombo-embolic events. Today, therapy is based on surgery and antibiotic therapy. When thromboembolic complications in IE patients persist, this is often due to our lack of knowledge regarding the pathophysiological development and organization of cells in the vegetation, most notably the primordial role of platelets and further triggered hemostasis, which is related to the diversity of infectious microorganisms involved. Our objective was to study the organization of IE vegetations due to different bacteria species in order to understand the related pathophysiological mechanism of vegetation development. We present an approach for ultrastructural analysis of whole-infected heart valve tissue based on scanning electron microscopy and energy-dispersive X-ray spectroscopy. Our approach allowed us to detect differences in cell organization between the analyzed vegetations and revealed a distinct chemical feature in Topics: Aged; Aged, 80 and over; Blood Platelets; Endocarditis, Bacterial; Female; Fibrin; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Heart Valves; Humans; Inflammation; Male; Microscopy, Electron, Scanning; Middle Aged; Spectrometry, X-Ray Emission | 2020 |
Inflammatory cell profile using different autologous fibrin protocols.
Autologous fibrin has been widely used in surgical procedures for both soft and hard tissue repair. There are different protocols and devices to obtain this matrix, with varying centrifugal time, gravity force, speed, angle of the sample tube and spinning radius. The aim of this study was to compare three methods of obtaining autologous fibrin: L-PRF using the Intra-Spin L-PRF centrifuge (Dohan protocol), the advanced PRF (A-PRF) using the Intra-Spin L-PRF centrifuge and autologous leukocyte fibrin (ALF), using the Kasvi centrifuge. Venous blood was collected from 7 healthy volunteers, which were submitted to the 3 different methods of centrifugation. The membranes were tissue-processed and evaluated by immunohistochemistry for CD3, CD20, CD68 and CD138. For CD68+, a lower number of cells was immunolabelled in the L-PRF group when compared to the other groups (A-PRF and ALF). For CD3+, a lower number of immunolabellated cells was observed in the ALF group when compared to the remaining groups (p < 0.05). In the A-PRF group, the CD20+ cell count was lower than in the remaining groups. No difference was observed in CD138+ cell counts between the groups. The 3 protocols tested are suitable for obtaining autologous fibrin membranes. Topics: Antigens, CD; Cell Count; Fibrin; Humans; Inflammation; Leukocytes; Platelet-Rich Fibrin | 2020 |
Development of fibrin hydrogel-based in vitro bioassay system for assessment of skin permeability to and pro-inflammatory activity mediated by zinc ion released from nanoparticles.
Nanoparticles (NPs) are promising products in industry and medicine due to their unique physicochemical properties. In particular, zinc oxide (ZnO) NPs are extensively incorporated into sunscreens to protect the skin from exposure to ultraviolet radiation. However, there are several health concerns about skin penetration and the resultant toxicity. As methodologies for evaluating NP toxicity are under development, it is difficult to fully assess the toxicity of ZnO NPs toward humans. In this study, we developed a platform to simultaneously detect skin permeability to and pro-inflammatory activity mediated by zinc ion released from NPs. First, we generated a stable reporter cell line expressing green fluorescent protein (GFP) under the control of interleukin-8 (IL-8) promoter activity. The expression levels of GFP induced by zinc reflected the endogenous IL-8 expression levels and the pro-inflammatory responses. Next, we found that fibrin hydrogel can reproduce permeability to zinc ion of a human skin equivalent model and is therefore a promising material to assess skin permeability to zinc ion. Then, we constructed a fibrin hydrogel-based in vitro bioassay system for the simultaneous detection of skin permeability to and pro-inflammatory activity mediated by zinc ion released from NPs by using a stable reporter cell line and a fibrin hydrogel layer. This bioassay system is a promising in vitro permeation test due to its technical simplicity and good predictability. Overall, we believe that our bioassay system can be widely used in the cosmetics and pharmaceutical industries. Topics: Alginates; Biological Assay; Cell Line; Collagen; Fibrin; Humans; Hydrogels; In Vitro Techniques; Inflammation; Interleukin-8; Metal Nanoparticles; Permeability; Skin; Tumor Necrosis Factor-alpha; Zinc | 2020 |
Quantitative Morphology of Cerebral Thrombi Related to Intravital Contraction and Clinical Features of Ischemic Stroke.
The purpose was to assess quantitatively and qualitatively the composition and structure of cerebral thrombi and correlate them with the signs of intravital clot contraction (retraction), as well as with etiology, severity, duration, and outcomes of acute ischemic stroke.. We quantified high-resolution scanning electron micrographs of 41 cerebral thrombi for their detailed cellular and noncellular composition and analyzed histological images for the overall structure with the emphasis on red blood cell compression, fibrin age, and the signs of inflammation.. Cerebral thrombi were quite compact and had extremely low porosity. The prevailing cell type was polyhedral compressed erythrocytes (polyhedrocytes) in the core, and fibrin-platelet aggregates were concentrated at the periphery; both findings are indicative of intravital contraction of the thrombi. The content of polyhedrocytes directly correlated with the stroke severity. The prevalence of fibrin bundles was typical for more severe cases, while the content of fibrin sponge prevailed in cases with a more favorable course. The overall platelet content in cerebral thrombi was surprisingly small, while the higher content of platelet aggregates was a marker of stroke severity. Fibrillar types of fibrin prevailed in atherothrombogenic thrombi. Older fibrin prevailed in thrombi from the patients who received thrombolytics, and younger fibrin dominated in cardioembolic thrombi. Alternating layers of erythrocytes and fibrin mixed with platelets were common for thrombi from the patients with more favorable outcomes. Thrombi with a higher number of leukocytes were associated with fatal cases.. Most cerebral thrombi undergo intravital clot contraction (retraction) that may be of underestimated clinical importance. Despite the high variability of the composition and structure of cerebral thrombi, the content of certain types of blood cells and fibrin structures combined with the morphological signs of intravital contraction correlate with the clinical course and outcomes of acute ischemic stroke. Topics: Aged; Blood Platelets; Cell Shape; Clot Retraction; Embolic Stroke; Erythrocytes; Female; Fibrin; Fibrinolytic Agents; Humans; Inflammation; Ischemic Stroke; Male; Microscopy, Electron, Scanning; Severity of Illness Index; Thrombectomy; Thrombotic Stroke | 2020 |
Detection of Citrullinated Fibrin in Plasma Clots of Rheumatoid Arthritis Patients and Its Relation to Altered Structural Clot Properties, Disease-Related Inflammation and Prothrombotic Tendency.
The risk of cardiovascular events in patients with Rheumatoid Arthritis (RA) is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmune-associated citrullination on the structure and thrombotic potential of fibrin(ogen) remains unknown. We therefore compared indices of vascular function, inflammation, coagulation and fibrin clot composition in RA patients with healthy controls and evaluated parameter association with disease presence.. Blood samples were collected from 30 RA patients and 30 age- and gender-matched healthy volunteers. Levels of serum amyloid A (SAA), c-reactive protein (CRP), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography (TEG. Concentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation, rate of fibrin cross-linking, and time to reach maximum thrombus generation were attenuated in RA patients. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls and multiple citrullinated regions within fibrin clot structures in RA patients were present.. Our findings provide novel evidence for the citrullination of fibrin within vasculature is more prominent in RA plasma compared to control plasma and plasma is more accessible than synovial fluid. Citrullinated fibrinogen could play a role as a determinant of thrombotic risk in RA patients. Topics: Adult; Aged; Arthritis, Rheumatoid; Blood Coagulation; C-Reactive Protein; Citrullination; Female; Fibrin; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Serum Amyloid A Protein; Thrombosis; Up-Regulation; Young Adult | 2020 |
Protective effect of pterostilbene on concanavalin A-induced acute liver injury.
Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Fibrin; Gene Expression Regulation; Humans; Inflammation; Macrolides; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Specific Pathogen-Free Organisms; Stilbenes; Thromboplastin | 2019 |
Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability.
Inflammation and thrombosis are integrated, mutually reinforcing processes, but the interregulatory mechanisms are incompletely defined. Here, we examined the contribution of α-defensins (α-defs), antimicrobial proteins released from activated human neutrophils, on clot formation in vitro and in vivo. Activation of the intrinsic pathway of coagulation stimulates release of α-defs from neutrophils. α-Defs accelerate fibrin polymerization, increase fiber density and branching, incorporate into nascent fibrin clots, and impede fibrinolysis in vitro. Transgenic mice (Def Topics: alpha-Defensins; Animals; Blood Coagulation; Fibrin; Fibrinolysis; Humans; Inflammation; Kallikreins; Male; Mice; Neutrophil Activation; Protein Conformation; Protein Stability; Thrombosis | 2019 |
Fibrin Modulates Shear-Induced NETosis in Sterile Occlusive Thrombi Formed under Haemodynamic Flow.
Neutrophils can release extracellular traps (NETs) in infectious, inflammatory and thrombotic diseases. NETs have been detected in deep vein thrombosis, atherothrombosis, stroke, disseminated intravascular coagulation and trauma. We have previously shown that haemodynamic forces trigger rapid NETosis within sterile occlusive thrombi in vitro. Here, we tested the effects of thrombin, fibrin and fibrinolysis on shear-induced NETosis by imaging NETs with Sytox Green during microfluidic perfusion of factor XIIa-inhibited or thrombin-inhibited human whole blood over fibrillar collagen (±tissue factor). For perfusions under venous pressure drops (19 mm Hg/mm-clot), thrombin generation did not alter the near-zero level of NET generation. In contrast, production of thrombin/fibrin led to a twofold reduction in neutrophil accumulation and a sixfold reduction in NET generation after 30 minutes of arterial perfusion (163 mm Hg/mm-clot). Exogenously added tissue type plasminogen activator (tPA) drove robust fibrinolysis; however, tPA did not trigger NETosis under venous flow. In contrast, tPA did enhance NET generation in clots subjected to arterial pressure drops. After 45 minutes of arterial perfusion, clots treated with 30 nM tPA had a threefold increase in total NET production and a twofold increase in normalized NET generation (measured as deoxyribonucleic acid:neutrophil) compared with fibrin-rich clots. Blocking fibrin polymerization resulted in similar level of NET release seen in tPA-treated clots, whereas ε-aminocaproic acid abolished the NET-enhancing effect of tPA. Therefore, fibrin suppresses NET generation and the absence of fibrin promotes NETs. We demonstrated that shear-induced NETosis was strongly inversely correlated with fibrin in sterile occlusive clots. Topics: Blood Coagulation; Blood Platelets; Extracellular Traps; Factor VIIa; Fibrin; Fibrinolysis; Hemodynamics; Humans; Inflammation; Microfluidics; Microscopy, Fluorescence; Neutrophils; Organic Chemicals; Shear Strength; Thrombin; Thrombosis | 2019 |
Nanostructured fibrin agarose hydrogel as a novel haemostatic agent.
Blood loss remains a major concern during surgery and can increase the morbidity of the intervention. The use of topical haemostatic agents to overcome this issue therefore becomes necessary. Fibrin sealants are promising haemostatic agents due to their capacity to promote coagulation, but their effectiveness and applicability need to be improved. We have compared the haemostatic efficacy of a novel nanostructured fibrin-agarose hydrogel patch, with (c-NFAH) or without cells (a-NFAH), against two commercially available haemostatic agents in a rat model of hepatic resection. Hepatic resections were performed by making short or long incisions (mild or severe model, respectively), and haemostatic agents were applied to evaluate time to haemostasis, presence of haematoma, post-operative adhesions to adjacent tissues, and inflammation factors. We found a significantly higher haemostatic success rate (time to haemostasis) with a-NFAH than with other commercial haemostatic agents. Furthermore, other relevant outcomes investigated were also improved in the a-NFAH group, including no presence of haematoma, lower adhesions, and lower grades of haemorrhage, inflammation, and necrosis in histological analysis. Overall, these findings identify a-NFAH as a promising haemostatic agent in liver resection and likely in a range of surgical procedures. Topics: Animals; Fibrin; Hemorrhage; Hemostatics; Hydrogels; Inflammation; Liver; Male; Nanostructures; Necrosis; Rats, Wistar; Sepharose | 2019 |
Preparation of fibrin hydrogels to promote the recruitment of anti-inflammatory macrophages.
Macrophages play an important role in regulating inflammation and tissue regeneration. In the present study, uniform fibrin hydrogel scaffolds were engineered in millimeters. These scaffolds induced anti-inflammatory macrophages to digest and infiltrate the scaffold. The culture conditions of the fibrin hydrogels decreased the secretion of tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, and increased the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, in mouse bone marrow-derived macrophages. Similar results were also observed in human monocyte-derived macrophages (HMDMs). In addition, most of cells that infiltrated the fibrin hydrogels were macrophages expressing CD163, CD204, and CD206, which are anti-inflammatory macrophages markers, both in mice and in human cells. Therefore, to induce increased macrophage infiltration, we attempted to combine fibrin hydrogels with SEW2871, a monocyte/macrophage recruitment agent that is known to be a sphingosine-1 phosphate receptor 1 agonist, solubilized in water by micelle formation with a cholesterol-grafted gelatin. However, the fibrin hydrogels alone retained the same monocyte migration activity as the hydrogels with SEW2871-incorporated micelles in the hydrogel-bearing mouse model. These findings indicate that fibrin hydrogels have a strong promoting effect on the recruitment of anti-inflammatory macrophages. Therefore, fibrin hydrogels may be an optimal biomaterial in the design of medicines for macrophage-induced regenerative therapies. STATEMENT OF SIGNIFICANCE: The immune response to tissue injury is important for determining the speed and the result of the regeneration. Alternatively activated macrophages (M2 macrophages) resolve inflammatory response and promote tissue repair by producing anti-inflammatory factors. Promoting the recruitment of macrophages is a hopeful strategy in the design of biomaterials for tissue regeneration. In the present study, we combined the fibrin hydrogel, which promotes anti-inflammatory polarization, with a macrophage recruitment agent. We revealed that the fibrin hydrogel significantly promoted anti-inflammatory polarization in mouse in vivo and human in vitro. Moreover, macrophages significantly infiltrated into the fibrin hydrogel regardless of the agent combination. Fibrin hydrogels may become a reliable biomaterial for tissue regeneration, and the present study is believed to provide information for many researchers. Topics: Animals; Antigens, CD; Fibrin; Gene Expression Regulation; Hydrogels; Inflammation; Interleukin-10; Macrophages; Male; Mice; Oxadiazoles; Thiophenes; Tumor Necrosis Factor-alpha | 2019 |
Staphylococcus aureus endocarditis: distinct mechanisms of bacterial adhesion to damaged and inflamed heart valves.
The pathogenesis of endocarditis is not well understood resulting in unsuccessful attempts at prevention. Clinical observations suggest that Staphylococcus aureus infects either damaged or inflamed heart valves. Using a newly developed endocarditis mouse model, we therefore studied the initial adhesion of S. aureus in both risk states.. Using 3D confocal microscopy, we examined the adhesion of fluorescent S. aureus to murine aortic valves. To mimic different risk states we either damaged the valves with a surgically placed catheter or simulated valve inflammation by local endothelium activation. We used von Willebrand factor (VWF) gene-deficient mice, induced platelet and fibrinogen depletion and used several S. aureus mutant strains to investigate the contribution of both host and bacterial factors in early bacterial adhesion. Both cardiac valve damage and inflammation predisposed to endocarditis, but by distinct mechanisms. Following valve damage, S. aureus adhered directly to VWF and fibrin, deposited on the damaged valve. This was mediated by Sortase A-dependent adhesins such as VWF-binding protein and Clumping factor A. Platelets did not contribute. In contrast, upon cardiac valve inflammation, widespread endothelial activation led to endothelial cell-bound VWF release. This recruited large amounts of platelets, capturing S. aureus to the valve surface. Here, neither fibrinogen, nor Sortase A were essential.. Cardiac valve damage and inflammation predispose to S. aureus endocarditis via distinct mechanisms. These findings may have important implications for the development of new preventive strategies, as some interventions might be effective in one risk state, but not in the other. Topics: Animals; Aortic Valve; Bacterial Adhesion; Blood Platelets; Coagulase; Disease Models, Animal; Endocarditis, Bacterial; Endothelium; Female; Fibrin; Inflammation; Male; Mice; Platelet Membrane Glycoproteins; Staphylococcal Infections; Staphylococcus aureus; von Willebrand Factor | 2019 |
Resveratrol-Coated Balloon Catheters in Porcine Coronary and Peripheral Arteries.
Angioplasty aiming at vascular dilatation causes endothelial denudation and induces complex inflammatory responses that affect vascular healing, including delayed reendothelialization and excessive neointima proliferation. Resveratrol is known for multiple beneficial effects on the vessel wall after systemic treatment or sustained release from a stent. It is also used as an additive on drug-coated balloon catheters (DCB). In this study, the effect of a single dose of resveratrol, three days to four weeks after administration as a balloon coating during angioplasty, was investigated. Sixteen pigs underwent angioplasty with resveratrol-coated or uncoated balloon catheters in coronary and peripheral arteries. Vessels were overstretched by approximately 20% to enhance vessel wall injury and to produce persistent vessel wall irritation. A significantly reduced number of micro vessels and macrophages in the adventitia, as well as an improved reendothelialization of the vessel lumen, were observed in resveratrol-treated peripheral arteries. The coronaries had a much higher injury score compared to peripheral vessels. Resveratrol-dependent reduction of macrophages, micro vessels or acceleration of reendothelialization was not evident in the coronary vessels. Additionally, no significant effect on neointima proliferation and inflammation score in either vessel territory was observed as a result of resveratrol treatment. In conclusion, the results suggest that resveratrol diminishes the inflammatory response and promotes vascular healing in peripheral arteries. These same effects are absent in more severely injured coronary arteries. Topics: Animals; Cardiac Catheters; Catheterization, Peripheral; Coated Materials, Biocompatible; Coronary Vessels; Fibrin; Inflammation; Macrophages; Resveratrol; Swine | 2019 |
Mitigation of monocyte driven thrombosis on cobalt chrome surfaces in contact with whole blood by thin film polar/hydrophobic/ionic polyurethane coatings.
Monocytes are active at the crossroads between inflammation and coagulation processes since they can secrete pro-inflammatory cytokines and express tissue factor (TF), a major initiator of coagulation. Cobalt-chrome (CoCr), a metal alloy, used as a biomaterial for vascular stents, has been shown to be potentially pro-thrombotic and pro-inflammatory. Research work with a polymer from a family of degradable-polar hydrophobic ionic polyurethanes (D-PHI), called HHHI, has been shown to exhibit anti-inflammatory responses from human monocytes. We have generated multifunctional polyurethane thin films (MPTF) based on the HHHI chemistry, as a thin coating for CoCr and have evaluated the reactivity of blood with MPTF-coated CoCr. The results showed that the coating of CoCr with MPTF derived from HHHI prevents thrombin generation, reduces coagulation activation, and suppresses fibrin formation in whole blood. Activation of monocytes was also suppressed at the surface of MPTF-coated CoCr and specifically the decrease in thrombin generation was accompanied by a significant decrease in TF and pro-inflammatory cytokine levels. Mass spectroscopy of the adsorbed proteins showed lower levels of fibrinogen, fibronectin and complement C3, C4, and C8 when compared to CoCr. We can conclude that MPTFs reduce the pro-thrombotic and pro-inflammatory phenotype of monocytes and macrophages on CoCr, and prevent clotting in whole blood. Topics: Cell Shape; Chromium Alloys; Coated Materials, Biocompatible; Fibrin; Humans; Hydrophobic and Hydrophilic Interactions; Inflammation; Inflammation Mediators; Ions; Macrophages; Monocytes; Polyurethanes; Principal Component Analysis; Surface Properties; Thrombin; Thromboplastin; Thrombosis; Tumor Necrosis Factor-alpha | 2019 |
The myeloperoxidase product, hypochlorous acid, reduces thrombus formation under flow and attenuates clot retraction and fibrinolysis in human blood.
Hypochlorite (HOCl), a strong oxidant and antimicrobial agent, has been proposed to be associated with hemostatic abnormalities during inflammatory response. However, its complex impact on hemostasis is not completely understood. In this report we studied the effect of clinically relevant (micromolar) HOCl concentrations on thrombus formation under flow, kinetics of platelet-fibrin clot formation, its architecture, retraction, and lysis. We found that HOCl (up to 500 µM) did not affect kinetics of coagulation measured in whole blood. HOCl (500-1000 µM) markedly diminished thrombus formation under flow. Clot retraction rate was reduced by HOCl dose-dependently (50-500 µM). HOCl (125-500 µM) inhibited fibrinolysis in whole blood and in platelet-depleted plasma, dose-dependently. Activity of plasmin was reduced by HOCl at concentrations started from 500 µM. HOCl (up to 500 µM) did not reduce plasminogen binding to fibrin under flow. HOCl (125-500 µM) modulated architecture of fibrin- and platelet-fibrin clots towards structures made of thin and densely packed fibers. Exposure of pure fibrinogen to HOCl (10-1000 µM) resulted in formation of dityrosine and was associated with altered fibrin structure derived from such modified fibrinogen. HOCl-altered fibrin net structure was not related with modulation of platelet procoagulant response, thrombin generation, and factor XIII activity. We conclude that, in human blood, clinically relevant HOCl concentrations may inhibit thrombus formation under flow, clot retraction and fibrinolysis. Fibrinolysis and clot retraction seem to be the most sensitive to HOCl-evoked inhibition. HOCl-modified fibrinogen and altered clot structure associated with it are likely to be primary sources of attenuated fibrinolysis. Topics: Blood Coagulation; Blood Platelets; Clot Retraction; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Hypochlorous Acid; Inflammation; Peroxidase; Thrombin; Thrombosis | 2019 |
pH influences the biocompatibility of methylene blue solutions.
The aim of this study was to investigate the biocompatibility of methylene blue at different pH levels through the method of implantation in subcutaneous tissue.. Eighty-four sterilized polyethylene tubes were allocated in the subcutaneous tissue of 28 rats, each one receiving four tubes, set into four groups: group tube (G-T)-empty tube, fibrin group (G-F)-tube filled with fibrin sponge, group methylene blue pH 7 (G-MB/pH 7)-tube filled with fibrin sponge soaked by methylene blue (100 μg/ml) at pH 7.0, and group methylene blue pH 1 (G-MB/pH 1)-tube filled with fibrin sponge and soaked by methylene blue (100 μg/ml) at pH 1.0. After 7, 15, and 30 days, seven animals from each group were euthanized, and the tubes involved by the surrounding tissue were removed and fixed with 4% buffered formaldehyde solution. The collected pieces were processed and histological sections (4 μm) were stained with hematoxylin and eosin and analyzed by light microscopy. Scores were assigned to analysis of histopathologic parameters. The results were statistically analyzed by the Kruskal-Wallis test (p ≤ 0.05).. At 7 and 30 days, the G-MB/pH 1 group showed no significant difference in the G-T control group, while G-MB/pH 7 had a significant increase on tissue reaction, also when compared to G-T. At 15 days, there was no statistical difference between the groups.. Within the limits of this study, it is concluded that methylene blue at pH 1.0 provides better biocompatibility than at pH 7.0. Topics: Animals; Biocompatible Materials; Fibrin; Hydrogen-Ion Concentration; Inflammation; Lymphocytes; Macrophages; Materials Testing; Methylene Blue; Rats; Rats, Wistar; Solutions; Subcutaneous Tissue | 2018 |
Initial pathological responses of second-generation everolimus-eluting stents implantation in Japanese coronary arteries: Comparison with first-generation sirolimus-eluting stents.
The clinical benefit of second-generation drug-eluting stents (2nd DES) has been established, compared to first-generation drug-eluting stents (1st DES). However, pathological response after 2nd DES implantation remains unclear, particularly in the Japanese population.. Using specimens obtained by autopsy, we compared the histology between 2nd DES (41 sections) and 1st DES (38 sections) lesions within 1 year after stent implantation to evaluate early tissue reaction in Japanese patients. Stent segments were fixed with 10% buffered formalin and embedded in plastic, followed by hematoxylin-eosin and Masson's trichrome staining. Ratio of covered stent struts was calculated, and the area of fibrin deposition was morphometrically evaluated. The degree of inflammation around struts was examined semi-quantitatively (score 0-3).. The ratio of covered struts and mean fibrin area of 2nd DES were 0.69±0.05 and 658.0±173.4μm. Histopathological analysis showed advanced healing process in 2nd DES compared with 1st DES lesions. These results are consistent with clinical beneficial outcome of 2nd DES implantation. Topics: Aged; Aneurysm, Ruptured; Colitis, Ischemic; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Fibrin; Heart Failure; Humans; Inflammation; Japan; Male; Middle Aged; Neointima; Pancreatitis; Pneumonia; Renal Insufficiency; Risk Factors; Sepsis; Sirolimus; Treatment Outcome | 2018 |
Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1β, IL-6 and IL-8.
Circulating cytokines, and particularly the interleukin (IL)-family are known to play an important role in inflammation. These molecules circulate in the blood and therefore have a direct effect on the plasma molecules and the formed elements like the erythrocytes and platelets. Aberrant coagulation (hypercoagulation or blood clots that form too easily) and clot lyses (hypofibrinolysis, where clots do not dissolve properly, with an abnormally low rate of clot lysis time), are usually the hallmarks of many inflammatory conditions. However, the mechanism by which cross-linking augments clot stiffness remains undetermined. IL-1β; IL-6 and IL-8 has been found to be involved in most chronic and acute inflammatory diseases. In the present study, we investigate clot structure of healthy blood, with the addition of these 3 interleukins, to determine the individual effects at concentrations that mimic low-grade, chronic inflammation. Previous studies showed that clot rheological behavior is regulated by at least the following three factors, fibrinogen concentration, fibrin network architecture and FXIIIa-induced ligation. We investigated clot formation and lysis using thromboelastography (TEG), before and after exposure, and created clots by adding thrombin to whole blood. This allowed us to look at extensive fibrin fiber formation and their interactions with particularly the erythrocytes, using scanning electron microscopy (SEM). Our results showed that IL-1β; IL-6 and IL-8 causes hypercoagulation and results in a disheveled fibrin clot, with trapped RBCs. IL-8 showed eryptosis (a type of apoptosis in erythrocytes). Our lysis results showed that both clot lysis time and maximum rate of lysis are decreased, with the addition of the interleukins. This is a novel finding and the observations reported in this paper, therefore points to the importance of looking at the effects of individual circulating inflammagens, to better understand the role that each play in the expression of disease. These methods can be used for an individualized patient-orientated approach in healthcare to track blood viscosity in conditions with acute and chronic inflammation. Topics: Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Erythrocytes; Fibrin; Fibrin Clot Lysis Time; Fibrinogen; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Thrombin | 2018 |
Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI.
Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU) for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28- and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 5'-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients. Topics: Biomarkers; Burns; Disease Progression; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Inflammation; Inflammatory Bowel Diseases; Mortality; Platelet Activation; Platelet Count; Platelet Membrane Glycoproteins; Predictive Value of Tests; Sepsis; Solubility | 2018 |
Neutrophil Elastase-Derived Fibrin Degradation Products Indicate Presence of Abdominal Aortic Aneurysms and Correlate with Intraluminal Thrombus Volume.
The intraluminal thrombi (ILT) of abdominal aortic aneurysms (AAA) contain neutrophils, which can secrete elastase. We evaluated whether plasma neutrophil elastase-derived cross-linked fibrin degradation products (E-XDP) could reveal the presence, size and mechanical stress of AAAs and its ILTs.. E-XDP levels were elevated in patients with AAA compared with controls (. E-XDP is a marker of the presence of AAA and coexisting aneurysms as well as the volume and mechanical stress of the ILT. Topics: Aged; Aorta; Aortic Aneurysm, Abdominal; Case-Control Studies; Fibrin; Fibrin Fibrinogen Degradation Products; Finite Element Analysis; Humans; Inflammation; Leukocyte Elastase; Male; Middle Aged; Multivariate Analysis; Retrospective Studies; Stress, Mechanical; Thrombosis | 2018 |
Chronic Intraocular Inflammation as a Risk Factor for XEN Gel Stent Occlusion: A Case of Microscopic Examination of a Fibrin-obstructed XEN Stent.
In recent years microinvasive glaucoma surgery has risen in popularity. Among microinvasive glaucoma surgery options is the XEN gel stent (Allergan Plc, Dublin, Ireland), a 45 μm wide ab-interno microstent. It has proven effective in lowering intraocular pressure (IOP) with low complication rates. However, XEN gel stents can become obstructed and cause postoperative rise in IOP. The causes and predicting factors for such obstructions still requires further research.. We describe the case of a 69-year-old male patient, with traumatic glaucoma and chronic intraocular inflammation showed by laser flare photometry, following childhood trauma and anterior segment surgery. Uncontrollable IOP despite maximal antiglaucomatous therapy was managed with XEN-augmented Baerveldt surgery. Despite good initial filtration and IOP control, the XEN stent became obstructed and was surgically replaced. After a month, the new stent became obstructed and was replaced by a thicker-lumened Baerveldt tube. This restored good filtration, and adequate IOP was maintained postoperatively. Microscopic examination of the obstructed XEN stent showed a dense fibrin plug.. This case report shows that fibrin formation could be an important factor in XEN gel stent obstruction, even in initially successfully filtering stents. The association of fibrinogenesis and intraocular inflammation could add a note of caution to the use of XEN gel stents in complicated cataract surgery, or advocate for aggressive anti-inflammatory treatments postoperatively. This could lead to a refinement in success predictors and better patient selection for XEN surgery. Finally, this could open the way to new management options for persistent obstructions, including pharmaceutical fibrinolysis. Topics: Aged; Chronic Disease; Device Removal; Fibrin; Fibrinolysis; Glaucoma; Glaucoma Drainage Implants; Humans; Inflammation; Intraocular Pressure; Male; Ophthalmologic Surgical Procedures; Prosthesis Failure; Prosthesis Implantation; Risk Factors; Stents; Tonometry, Ocular; Treatment Outcome | 2018 |
Phospholipase D1 regulation of TNF-alpha protects against responses to LPS.
Sepsis is a systemic inflammatory disorder with organ dysfunction and represents the leading cause of mortality in non-coronary intensive care units. A key player in septic shock is Tumor Necrosis Factor-alpha (TNF-α). Phospholipase (PL)D1 is involved in the regulation of TNF-α upon ischemia/reperfusion injury in mice. In this study we analyzed the impact of PLD1 in the regulation of TNF-α, inflammation and organ damage in experimental sepsis. PLD1 deficiency increased survival of mice and decreased vital organ damage after LPS injections. Decreased TNF-α plasma levels and reduced migration of leukocytes and platelets into lungs was associated with reduced apoptosis in lung and liver tissue of PLD1 deficient mice. PLD1 deficient platelets contribute to preserved outcome after LPS-induced sepsis because platelets exhibit an integrin activation defect suggesting reduced platelet activation in PLD1 deficient mice. Furthermore, reduced thrombin generation of PLD1 deficient platelets might be responsible for reduced fibrin formation in lungs suggesting reduced disseminated intravascular coagulation (DIC). The analysis of Pld1 Topics: Animals; Apoptosis; Blood Platelets; Cell Movement; Cells, Cultured; Disease Models, Animal; Fibrin; Immunity, Innate; Inflammation; Leukocytes; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Phospholipase D; Platelet Activation; Shock, Septic; Tumor Necrosis Factor-alpha | 2018 |
Correlative Light-Electron Microscopy detects lipopolysaccharide and its association with fibrin fibres in Parkinson's Disease, Alzheimer's Disease and Type 2 Diabetes Mellitus.
Many chronic diseases, including those classified as cardiovascular, neurodegenerative, or autoimmune, are characterized by persistent inflammation. The origin of this inflammation is mostly unclear, but it is typically mediated by inflammatory biomarkers, such as cytokines, and affected by both environmental and genetic factors. Recently circulating bacterial inflammagens such as lipopolysaccharide (LPS) have been implicated. We used a highly selective mouse monoclonal antibody to detect bacterial LPS in whole blood and/or platelet poor plasma of individuals with Parkinson's Disease, Alzheimer's type dementia, or Type 2 Diabetes Mellitus. Our results showed that staining is significantly enhanced (P < 0.0001) compared to healthy controls. Aberrant blood clots in these patient groups are characterized by amyloid formation as shown by the amyloid-selective stains thioflavin T and Amytracker™ 480 or 680. Correlative Light-Electron Microscopy (CLEM) illustrated that the LPS antibody staining is located in the same places as where amyloid fibrils may be observed. These data are consistent with the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis in which bacterial inflammagens such as LPS are responsible for anomalous blood clotting as part of the aetiology of these chronic inflammatory diseases. Topics: Aged; Alzheimer Disease; Amyloid; Blood Coagulation; Blood Specimen Collection; Diabetes Mellitus, Type 2; Female; Fibrin; Humans; Inflammation; Lipopolysaccharides; Male; Microscopy, Electron; Middle Aged; Parkinson Disease; Protein Binding | 2018 |
Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex.
Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognized feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration.. A postmortem cohort of pathologically confirmed MS (n = 47) and control (n = 10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n = 20; control, n = 10), expression of plasminogen activator inhibitor 1 (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen).. Motor cortical fibrin(ogen) deposition was significantly over-represented in MS compared to control cases in all compartments studied (ie, extracellular [p = 0.001], cell body [p = 0.003], and neuritic/glial-processes [p = 0.004]). MS cases with high levels of extracellular fibrin(ogen) had significantly upregulated PAI-1 expression in all cortical layers assessed (p < 0.05) and reduced neuronal density (p = 0.017), including in the functionally-relevant layer 5 (p = 0.001).. For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259-270. Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Demyelinating Diseases; Female; Fibrin; Fibrinogen; Humans; Inflammation; Male; Middle Aged; Motor Cortex; Multiple Sclerosis, Chronic Progressive; Nerve Degeneration; Plasminogen Activator Inhibitor 1 | 2017 |
Thrombin promotes diet-induced obesity through fibrin-driven inflammation.
Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibγ390-396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte αMβ2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibγ390-396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients. Topics: Adipose Tissue; Adiposity; Amino Acid Motifs; Animals; Blood Glucose; Body Composition; Body Weight; Coagulants; Dabigatran; Diet, High-Fat; Fatty Liver; Female; Fibrin; Genotype; Homozygote; Inflammation; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Thrombin; Weight Gain | 2017 |
Effect of Chenopodium ambrosioides on the healing process of the in vivo bone tissue.
The focus of this double-blind randomized study was on evaluating the effect of an aqueous extract of Mastruz (Chenopodium ambrosioides L.) on the bone repair process in vivo. In total, 36 male Wistar rats were randomly selected for this study, and divided into 3 groups (n = 12): Group HS (Hemostatic Sponge), Group SM (Hemostatic Sponge with Mastruz) and Group BC (Blood Clot). In each animal, bone defects measuring 2 mm in diameter were performed in both tibias for placement of the substances. After 3 and 10 days, the animals were sacrificed, and the tissues were analyzed under an optical microscope relative to the following events: inflammatory infiltrate; necrosis; young fibroblasts; osteoclastic and osteoblastic activity; endosteal and periosteal bone formation; and bone repair. The results were assessed by using Kruskal-Wallis and Mann-Whitney tests (p < .05). Inflammatory infiltrate demonstrated difference between Groups SM and BC in the time interval of 3 days (p = .004); an event related to the presence of the fibrin sponge and liquid of the extract, which induced a foreign body initial reaction. The presence of young fibroblasts (p = .003), osteoclastic (p = .003), and osteoblastic (p = .020) activity was statistically significant between Groups HS and BC in the time interval of 10 days; performance was related to the presence of the sponge within bone. As regards injured bone tissue repair, Group SM demonstrated a higher level of regenerative capacity (p = 0.004), due to a larger quantities of endosteal and periosteal bone formation, demonstrated in Group SM. The aqueous extract of mastruz stimulated bone neoformation, presenting wound closure with bone tissue at the end of 10 days. Topics: Animals; Bone and Bones; Bone Regeneration; Chenopodium ambrosioides; Double-Blind Method; Fibrin; Inflammation; Male; Necrosis; Osteogenesis; Phytotherapy; Plant Extracts; Random Allocation; Rats; Rats, Wistar; Wound Healing | 2017 |
Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.
Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses.. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia.. CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-κB (nuclear factor κB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells.. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. Topics: Animals; Antibodies, Blocking; Basigin; Blood Platelets; Blood-Brain Barrier; Brain Ischemia; Fibrin; Infarction, Middle Cerebral Artery; Inflammation; Intracranial Thrombosis; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Stroke; Treatment Outcome | 2017 |
VON WILLEBRAND FACTOR IMMUNOHISTOCHEMICAL STAINING QUANTITATIVE OPTICAL DENSITY PARAMETERS IN THE ENDOTHELIUM AND FIBRINOID OF THE PLACENTA DURING SECUNDINES INFLAMMATION AND CONCOMITANT IRON DEFICIENCY ANEMIA IN GRAVIDAS.
The aim of the research was to set the optical density quantitative parameters of the von Willebrand factor immunohistochemical staining (vWF) in the endothelium and fibrinoid of the placenta during the secundines inflammation concomitant with iron deficiency anemia in gravidas. The total number of 198 placentas was studied. The immunohistochemical technique was performed using the visualization of the primary antibodies to vWF with a diaminobenzidine dye polymer system. The optical density of the histochemical staining was measured by means of computer microdensitometry after the digital copies of the images had been obtained. All the cases of the secundines inflammation and the structures under study were found to have a significant increase in the optical density of the vWF immunohistochemical staining in the endothelium of the blood vessels as compared to the physiological pregnancy. Iron deficiency anemia in gravidas (IDAG) contributes to an increase in the indices of the inflammation, the highest data pertaining to the endothelial cells of the placental basal plate in chronic basal deciduitis. The optical density of the staining in the fibrinoid of the chorionic and basal plates during chronic forms of chorioamnionitis and basal deciduitis is higher than the optical density inherent in physiological pregnancy. The intensity of staining increases in presence of all the forms of inflammation on the background of IDAG in comparison with physiological pregnancy with placenta inflammation. Compared with IDAG in absence of the inflammatory processes, only chronic inflammatory processes reveal a change in indices. Consequently, the optical density of the staining significantly increases in the endothelium of blood vessels in all forms of the secundines inflammation, in comparison with the physiological pregnancy, whereas in fibrinoid the same process is reported only in chronic course. In this case, IDAG is accompanied by maximum levels of optical density in the endothelium and fibrinoid, whereas in chronic, the average indices are higher than those in acute forms. Topics: Anemia, Iron-Deficiency; Chorioamnionitis; Endothelium, Vascular; Female; Fibrin; Humans; Image Processing, Computer-Assisted; Inflammation; Placenta; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Factor | 2017 |
Neutrophil Extracellular Traps Promote Hypercoagulability in Patients With Sepsis.
Patients with sepsis commonly exhibit a hypercoagulability with high risk of venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) are found to trigger inflammation and coagulation. We aim to determine whether NETs promoted the hypercoagulability and early anticoagulation reduced NETs releasing during sepsis.. In this prospective study, septic patients between September 2013 and June 2015 were included. Patients of age <18 years, acute organ failure, pregnancy, coagulation disorders, receiving anticoagulation before admission were excluded. Blood was sampled in 52 sepsis and 10 non-sepsis patients and 40 healthy controls, clinical, and hematological parameters were collected. The ability of plasma and platelets to prime neutrophils to release NETs and contribution of NETs to coagulation were assessed. NETs releasing was compared in patients with or without early coagulation, and its correlation with the risk of VTE was also evaluated.. NETs formation in septic patients was significantly higher than controls and non-sepsis patients. Neutrophils from septic patients had significantly enhanced NETs releasing compared with those from controls or non-sepsis patients. Plasma or platelets obtained from patients induced control neutrophils to release NETs. Notably, NETs released by neutrophils from septic patients significantly increased the potency of control plasma to generate thrombin and fibrin, and this effect was attenuated by administration of DNase I. Post-treatment NETs releasing in septic patients receiving early anticoagulation within 6 h was significantly lower than patients without early anticoagulation. The NETs formation correlated positively with the VTE risk, rather than the parameters of inflammation or disease severity.. The systemic inflammation during sepsis primes neutrophils to release NETs with increased risk of VTE. Early anticoagulation (6 h) reduces NETs releasing and may improve the coagulopathy of septic patients. Topics: Adult; Aged; Blood Coagulation; Extracellular Traps; Female; Fibrin; Fluorescent Antibody Technique; Humans; Inflammation; Male; Middle Aged; Neutrophils; Prospective Studies; Sepsis; Thrombin; Thrombophilia | 2017 |
Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen.
Fibrin is a major component of the provisional extracellular matrix formed during tissue repair following injury, and enables cell infiltration and anchoring at the wound site. Macrophages are dynamic regulators of this process, advancing and resolving inflammation in response to cues in their microenvironment. Although much is known about how soluble factors such as cytokines and chemokines regulate macrophage polarization, less is understood about how insoluble and adhesive cues, specifically the blood coagulation matrix fibrin, influence macrophage behavior. In this study, we observed that fibrin and its precursor fibrinogen elicit distinct macrophage functions. Culturing macrophages on fibrin gels fabricated by combining fibrinogen with thrombin stimulated secretion of the anti-inflammatory cytokine, interleukin-10 (IL-10). In contrast, exposure of macrophages to soluble fibrinogen stimulated high levels of inflammatory cytokine tumor necrosis factor alpha (TNF-α). Macrophages maintained their anti-inflammatory behavior when cultured on fibrin gels in the presence of soluble fibrinogen. In addition, adhesion to fibrin matrices inhibited TNF-α production in response to stimulation with LPS and IFN-γ, cytokines known to promote inflammatory macrophage polarization. Our data demonstrate that fibrin exerts a protective effect on macrophages, preventing inflammatory activation by stimuli including fibrinogen, LPS, and IFN-γ. Together, our study suggests that the presentation of fibrin(ogen) may be a key switch in regulating macrophage phenotype behavior, and this feature may provide a valuable immunomodulatory strategy for tissue healing and regeneration.. Fibrin is a fibrous protein resulting from blood clotting and provides a provisional matrix into which cells migrate and to which they adhere during wound healing. Macrophages play an important role in this process, and are needed for both advancing and resolving inflammation. We demonstrate that culture of macrophages on fibrin matrices exerts an anti-inflammatory effect, whereas the soluble precursor fibrinogen stimulates inflammatory activation. Moreover, culture on fibrin completely abrogates inflammatory signaling caused by fibrinogen or known inflammatory stimuli including LPS and IFN-γ. Together, these studies show that the presentation of fibrin(ogen) is important for regulating a switch between macrophage pro- and anti-inflammatory behavior. Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Cell Adhesion; Cell Polarity; Cell Shape; Collagen; Cytokines; Cytoprotection; Cytoskeleton; Female; Fibrin; Fibrinogen; Gels; Inflammation; Interferon-gamma; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice, Inbred C57BL; Rats | 2017 |
Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.
Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given.. Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP. Topics: ADAMTS13 Protein; Adult; Blood Platelets; Child; Complement System Proteins; Consensus; Diagnosis, Differential; Erythrocytes; Female; Fibrin; Hematology; Hemolysis; Hemolytic-Uremic Syndrome; Humans; Inflammation; Platelet Aggregation; Platelet Count; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Recurrence; Remission Induction; Societies, Medical; Terminology as Topic; Thrombotic Microangiopathies; Treatment Outcome; von Willebrand Factor | 2017 |
Protease-activated receptor 2 exacerbates adenine-induced renal tubulointerstitial injury in mice.
Hypercoagulability is associated with chronic kidney disease (CKD). Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade are known to activate protease-activated receptor 2 (PAR2), and to cause inflammation and tissue injury. Although PAR2 is highly expressed in the kidney, it is unclear whether PAR2 plays a pathogenic role in CKD. To test this, we fed the mice lacking Par2 (F2rl1 Topics: Adenine; Animals; Enzyme-Linked Immunosorbent Assay; Factor V; Factor Xa; Fibrin; Fibrosis; Gene Expression Regulation; Inflammation; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Receptor, PAR-2; Renal Insufficiency, Chronic; Thromboplastin | 2017 |
Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin-6 dependent.
Essentials Cancer cachexia and cancer-associated thrombosis have not previously been mechanistically linked. We assessed thrombin generation and coagulation parameters in cachectic C26 tumor-bearing mice. C26 mice are hypercoagulable, partially corrected by blocking tumor derived interleukin-6. Coagulability and anti-inflammatory interventions may be clinically important in cancer cachexia.. Background Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer, which have not previously been mechanistically linked. The colon 26 (C26) carcinoma is a well-established mouse model of complications of advanced cancer cachexia, partially dependent on high levels of interleukin-6 (IL-6) produced by the tumor. Objectives To assess if cancer cachexia altered the coagulation state and if this was attributable to tumor IL-6 production. Methods In male BALB/c*DBA2 (F1 hybrid) mice with a C26 tumor we used modified calibrated automated thrombogram and fibrin generation (based on overall hemostatic potential) assays to assess the functional coagulation state, and also examined fibrinogen, erythrocyte sedimentation rate (ESR), platelet count, tissue factor pathway inhibitor (TFPI) and hepatic expression of coagulation factors by microarray. C26 mice were compared with non-cachectic NC26, pair-fed and sham control mice. IL-6 expression in C26 cells was knocked down by lentiviral shRNA constructs. Results C26 mice with significant weight loss and highly elevated IL-6 had elevated thrombin generation, fibrinogen, ESR, platelets and TFPI compared with all control groups. Fibrin generation was elevated compared with pair-fed and sham controls but not compared with NC26 tumor mice. Hepatic expression of coagulation factors and fibrinolytic inhibitors was increased. Silencing IL-6 in the tumor significantly, but incompletely, attenuated the increased thrombin generation, fibrinogen and TFPI. Conclusions Cachectic C26 tumor-bearing mice are in a hypercoagulable state, which is partly attributable to IL-6 release by the tumor. The findings support the importance of the coagulation state in cancer cachexia and the clinical utility of anti-inflammatory interventions. Topics: Animals; Blood Coagulation; Cachexia; Cell Line, Tumor; Disease Models, Animal; Fibrin; Fibrinogen; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin-6; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasm Transplantation; Neoplasms; Thrombin; Tissue Array Analysis | 2017 |
Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.
Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy. Topics: Adult; Aged; Biomarkers, Tumor; Case-Control Studies; Chronic Disease; Epstein-Barr Virus Infections; Female; Fibrin; Follow-Up Studies; Humans; Immunohistochemistry; Inflammation; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prognosis | 2017 |
The Alzheimer's disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII.
Essentials How the Alzheimer's disease (AD) peptide β-amyloid (Aβ) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Aβ triggers FXII-dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Aβ-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target.. Background β-Amyloid (Aβ) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein factor XII triggers clot formation via the intrinsic coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for Aβ to contribute to a prothrombotic state. Methods and results We show that Aβ activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing Aβ as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of Aβ to promote coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD. Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Blood Coagulation; Blood Flow Velocity; Cerebrovascular Circulation; Complement C1 Inhibitor Protein; Enzyme-Linked Immunosorbent Assay; Factor XII; Female; Fibrin; Healthy Volunteers; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Neurons; Thrombin; Thrombosis; Treatment Outcome | 2016 |
The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation.
ESSENTIALS: The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both in vitro and in vivo. These findings may represent a crossroad between the complement and the coagulation systems.. The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor in vitro. In vivo studies also show that MASP-1 is involved in thrombogenesis.. To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions.. Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2.. Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation.. MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation. Topics: Adult; Aged; Aged, 80 and over; Antithrombin Proteins; Blood Coagulation; Blood Platelets; Case-Control Studies; Complement C1 Inhibitor Protein; Complement Pathway, Mannose-Binding Lectin; Enzyme Activation; Female; Fibrin; Humans; Inflammation; Lupus Erythematosus, Systemic; Male; Mannose-Binding Protein-Associated Serine Proteases; Middle Aged; Multiple Trauma; Platelet Activation; Protein Binding; Signal Transduction; Thrombosis; Time Factors; Young Adult | 2016 |
Occurrence of fibronectin-fibrin complexes in plasma of patients with multimorbidity due to the inflamm-aging phenomenon.
Multimorbidity is the co-occurrence of chronic diseases associated with low-grade chronic inflammation of connective tissue.. Frequency of occurrence and relative amounts of fibronectin (FN) complexes with fibrin (FN-fibrin) and FN monomer were analyzed in 130 plasma samples of 18 to 94-year-old multimorbid patients in relation to concentrations of FN and extra domain A (EDA)-FN, and C-reactive protein (CRP) as well as to age, number of coexisting chronic diseases and presence of specified diseases.. Immunoblotting revealed, besides FN dimer, the presence of FN monomer, and 750-, 1000-, and 1300-kDa FN-fibrin complexes in the multimorbid plasmas. The FN-fibrin complexes appeared more frequently and in higher relative amounts, but FN monomer less frequently and in a lower relative amount in the groups of elderly multimorbid patients, with a higher number of coexisting diseases and with dominance of cardiovascular diseases and osteoarthrosis, and with CRP concentration of 3-5mg/l. In contrast, the normal plasma contained only the FN-fibrin complex of 750 kDa in a lower relative amount, but with an increasing amount with normal aging. Moreover, FN concentration increased and EDA-FN decreased with the number of co-existing diseases and aging of patients, although both concentration values were lower than in the age-matched normal groups. FN concentration was the lowest in the exacerbation of a chronic disease and EDA-FN in the stable chronic disease groups.. The alterations in plasma FN molecular status were associated with micro-inflammation and micro-coagulation, as well as multimorbidity of subjects and their physiological aging. Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; C-Reactive Protein; Chronic Disease; Comorbidity; Connective Tissue Diseases; Female; Fibrin; Fibronectins; Humans; Inflammation; Male; Middle Aged; Poland; Young Adult | 2016 |
Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism.
Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor αMβ2, we tested the hypothesis that disruption of the fibrin(ogen)-αMβ2 interaction in Fibγ(390-396A) mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, α-naphthylisothiocyanate (ANIT)-induced liver fibrosis increased in Fibγ(390-396A) mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fibγ(390-396A) mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fibγ(390-396A) mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)γ induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fibγ(390-396A) mice. Fibrin(ogen)-αMβ2 interaction inhibited iNOS induction in macrophages stimulated with IFNγ in vitro and ANIT-challenged IFNγ-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances αMβ2-dependent cell adhesion to fibrin. These studies characterize a novel mechanism whereby the fibrin(ogen)-integrin-αMβ2 interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease. Topics: 1-Naphthylisothiocyanate; Animals; Benzoates; Bile Ducts; Cell Adhesion; Female; Fibrin; Humans; Hyperplasia; Inflammation; Interferon-gamma; Liver Cirrhosis, Biliary; Macrophage-1 Antigen; Male; Mice; Mice, Knockout; Necrosis; Thiohydantoins | 2016 |
In Vitro and In Vivo Toxicity Evaluation of Colloidal Silver Nanoparticles Used in Endodontic Treatments.
Silver nanoparticles have been used for different purposes in dentistry, including endodontic treatments. The aim of this study was to determine the cytotoxicity of different types of silver nanoparticles on mouse fibroblast cell line L929 and the reaction of subcutaneous connective tissue of Wistar rats to these nanoparticles.. Silver nanoparticles of an average size of 5 nm were synthesized with ammonia (SNA) or polyvinylpyrrolidone (SNP). L929 was exposed to SNA and SNP (0.1-100 μg/mL), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assays were performed after 6, 24, and 48 hours. Culture medium was used as the control. Sixteen rats received, individually, 3 polyethylene tubes filled with a fibrin sponge embedded in 100 μL SNA or SNP (1 μg/mL). A fibrin sponge with no embedding was the control. Tissue reaction was performed qualitatively and quantitatively after 7, 15, 30, and 90 days of implantation in the dorsal connective tissue of Wistar rats.. SNA and SNP were cytotoxic to L929 in higher concentrations, with SNA significantly more toxic than SNP. SNA and SNP did not induce significant interleukin-1β and interleukin-6 production. The release of stem cell factor by L929 increased 48 hours after the treatment with SNP at 5 μg/mL. Histologic examination showed that the inflammatory responses caused by SNA and SNP at 1 μg/mL were similar to the control in all experimental periods.. It was concluded that SNA and SNP were not cytotoxic at 25 μg/mL or lower concentrations. However, for safe clinical use, further studies establishing others points of its toxicologic profile are recommended. Topics: Ammonia; Animals; Cell Line; Cell Survival; Connective Tissue; Dental Materials; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fibrin; Fibroblasts; Inflammation; Interleukin-1beta; Interleukin-6; Male; Materials Testing; Metal Nanoparticles; Mice; Microscopy, Electron, Transmission; Neutrophils; Particle Size; Porifera; Povidone; Rats; Rats, Wistar; Silver; Stem Cell Factor; Subcutaneous Tissue; Tetrazolium Salts; Thiazoles; Time Factors; Toxicity Tests | 2016 |
Morphogen and proinflammatory cytokine release kinetics from PRGF-Endoret fibrin scaffolds: evaluation of the effect of leukocyte inclusion.
The potential influence of leukocyte incorporation in the kinetic release of growth factors from platelet-rich plasma (PRP) may explain the conflicting efficiency of leukocyte platelet-rich plasma (L-PRP) scaffolds in tissue regeneration. To assess this hypothesis, leukocyte-free (PRGF-Endoret) and L-PRP fibrin scaffolds were prepared, and both morphogen and proinflammatory cytokine release kinetics were analyzed. Clots were incubated with culture medium to monitor protein release over 8 days. Furthermore, the different fibrin scaffolds were morphologically characterized. Results show that leukocyte-free fibrin matrices were homogenous while leukocyte-containing ones were heterogeneous, loose and cellular. Leukocyte incorporation produced a significant increase in the contents of proinflammatory cytokines interleukin (IL)-1β and IL-16 but not in the platelet-derived growth factors release (<1.5-fold). Surprisingly, the availability of vascular endothelial growth factor suffered an important decrease after 3 days of incubation in the case of L-PRP matrices. While the release of proinflammatory cytokines was almost absent or very low from PRGF-Endoret, the inclusion of leukocytes induced a major increase in these cytokines, which was characterized by the presence of a latent period. The PRGF-Endoret matrices were stable during the 8 days of incubation. The inclusion of leukocytes alters the growth factors release profile and also increased the dose of proinflammatory cytokines. Topics: Cell Adhesion; Cytokines; Epidermal Growth Factor; Fibrin; Hepatocyte Growth Factor; Humans; Hydrogels; Inflammation; Insulin; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Interleukin-16; Interleukin-1beta; Leukocytes; Optics and Photonics; Platelet-Derived Growth Factor; Platelet-Rich Plasma; Tissue Engineering; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A | 2015 |
Fibrin deposited in the Alzheimer's disease brain promotes neuronal degeneration.
Alzheimer's disease (AD) is the most common form of dementia and has no effective treatment. Besides the well-known pathologic characteristics, this disease also has a vascular component, and substantial evidence shows increased thrombosis as well as a critical role for fibrin(ogen) in AD. This molecule has been implicated in neuroinflammation, neurovascular damage, blood-brain barrier permeability, vascular amyloid deposition, and memory deficits that are observed in AD. Here, we present evidence demonstrating that fibrin deposition increases in the AD brain and correlates with the degree of pathology. Moreover, we show that fibrin(ogen) is present in areas of dystrophic neurites and that a modest decrease in fibrinogen levels improves neuronal health and ameliorates amyloid pathology in the subiculum of AD mice. Our results further characterize the important role of fibrin(ogen) in this disease and support the design of therapeutic strategies aimed at blocking the interaction between fibrinogen and amyloid-β (Aβ) and/or normalizing the increased thrombosis present in AD. Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Brain; Fibrin; Fibrinogen; Humans; Inflammation; Intracranial Thrombosis; Memory Disorders; Mice, Transgenic; Molecular Targeted Therapy; Nerve Degeneration; Neurites; Neurons | 2015 |
A dual delivery of substance P and bone morphogenetic protein-2 for mesenchymal stem cell recruitment and bone regeneration.
Implantation of ex vivo expanded and osteogenically differentiated mesenchymal stem cells (MSCs) for bone regeneration has drawbacks for clinical applications, such as poor survival of implanted cells and increased treatment expenses. As a new approach for bone regeneration that can circumvent these limitations, we propose dual delivery of substance P (SP) and bone morphogenetic protein-2 (BMP-2) to facilitate endogenous stem cell recruitment to bone defects by SP and subsequent in situ osteogenic differentiation of those cells by BMP-2. A heparin-conjugated fibrin (HCF) gel enabled dual delivery with fast release of SP and slow release of BMP-2, which would be ideal for prompt recruitment of endogenous stem cells in the first stage and time-consuming osteogenic differentiation of the recruited stem cells in the second stage. The HCF gels with SP and/or BMP-2 were implanted into mouse calvarial defects for 8 weeks. Local delivery of SP to the calvarial defects using HCF gel was more effective in recruiting MSCs to the calvarial defects than intraperitoneal or intravenous administration of SP. Many of the cells recruited by SP underwent osteogenic differentiation through local delivery of BMP-2. The efficacy of in vivo bone regeneration was significantly higher in the SP/BMP-2 dual delivery group. The dual delivery of SP and BMP-2 using the HCF gel therefore has potential as an effective bone regeneration strategy. Topics: Animals; Bone Morphogenetic Protein 2; Bone Regeneration; Cattle; Cell Differentiation; Cell Movement; Fibrin; Flow Cytometry; Heparin; Humans; Inflammation; Mesenchymal Stem Cells; Mice; Multipotent Stem Cells; Osteogenesis; Real-Time Polymerase Chain Reaction; Skull; Substance P; Tissue Scaffolds | 2015 |
Clinical and pathological characteristics of homogeneous and nonhomogeneous tissue of in-stent restenosis visualized by optical coherence tomography.
Although it is known that in-stent restenosis (ISR) patterns appear homogeneous or nonhomogeneous by optical coherence tomography (OCT), interpretations of the ISR inflammatory response, of the OCT image, and its pathological implications are unclear. The aim of this study was to use OCT to characterize ISR and its inflammatory index in patients after coronary stenting.. OCT was performed at follow-up in 100 angiographic ISR lesions. ISR lesions were divided into two groups: (a) homogeneous (n=48) and (b) nonhomogeneous (n=52) image groups. We assessed the ISR images produced by OCT for tissue heterogeneity and neo-intimal hyperplasia using the normalized standard deviation of OCT signal-intensity (OCT-NSD) observed in neo-intimal hyperplasia tissue. In some patients with a nonhomogeneous OCT image, we collected pathological tissue.. The prevalence of drug-eluting stents was 48% in the nonhomogeneous group and 29% in the homogeneous group (P=0.05). The OCT-NSD value in the nonhomogeneous group (0.223±0.019) was significantly higher than that in the homogeneous group (0.203±0.025; P<0.0001). Pathological tissue showed fibrin thrombi with infiltrating macrophage in 12 cases of nonhomogeneous ISR. The area under the receiver operating characteristic curve for the prediction of a nonhomogeneous image was 0.73 for OCT-NSD (95% confidence interval: 0.62-0.83: P<0.0001). The odds ratio for the prediction of a nonhomogeneous image was 3.47 (95% confidence interval: 1.18-10.2: P=0.02) for smoking by logistic regression analysis.. Nonhomogeneous ISR visualized by OCT showed a high OCT-NSD value, which was a useful predictor for nonhomogeneous images. Moreover, the nonhomogeneous ISR image visualized by OCT may show chronic inflammation and fibrin thrombi. Topics: Aged; Area Under Curve; Biomarkers; Biopsy; Chi-Square Distribution; Coronary Angiography; Coronary Restenosis; Coronary Thrombosis; Coronary Vessels; Drug-Eluting Stents; Female; Fibrin; Humans; Hyperplasia; Immunohistochemistry; Inflammation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neointima; Observer Variation; Odds Ratio; Percutaneous Coronary Intervention; Predictive Value of Tests; Prosthesis Design; Reproducibility of Results; Risk Factors; ROC Curve; Smoking; Tomography, Optical Coherence; Treatment Outcome | 2015 |
Leukocyte inclusion within a platelet rich plasma-derived fibrin scaffold stimulates a more pro-inflammatory environment and alters fibrin properties.
One of the main differences among platelet-rich plasma (PRP) products is the inclusion of leukocytes that may affect the biological efficacy of these autologous preparations. The purpose of this study was to evaluate whether the addition of leukocytes modified the morphological, biomechanical and biological properties of PRP under normal and inflammatory conditions. The release of pro-inflammatory cytokines from plasma rich in growth factors (PRGF) and leukocyte-platelet rich plasma (L-PRP) scaffolds was determined by enzyme-linked immunosorbent assay (ELISA) and was significantly increased under an inflammatory condition when leukocytes were included in the PRP. Fibroblasts and osteoblasts treated with L-PRP, under an inflammatory situation, underwent a greater activation of NFĸB pathway, proliferated significantly less and secreted a higher concentration of pro-inflammatory cytokines. These cellular events were assessed through Western blot and fluorimetric and ELISA methods, respectively. Therefore, the inclusion of leukocytes induced significantly higher pro-inflammatory conditions. Topics: Biomechanical Phenomena; Cell Proliferation; Cells, Cultured; Cytokines; Fibrin; Humans; Inflammation; Inflammation Mediators; Leukocytes; Materials Testing; NF-kappa B; Platelet-Rich Plasma; Regeneration; Signal Transduction; Tissue Scaffolds | 2015 |
Absence of nicotinic acetylcholine receptor α7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model.
Inflammation is regulated by endogenous mechanisms, including anti-inflammatory cytokines, adenosine, and the nicotinic acetylcholine receptor α7 subunit (α7nAChR). We investigated the role of α7nAChR in protection against the progression of tissue injury in a model of severe, macrophage-mediated, cytokine-dependent anti-glomerular basement membrane (GBM) glomerulonephritis (GN), in α7nAChR-deficient (α7(-/-)) mice . At d 7 after the injection of anti-GBM antibody, kidneys from α7(-/-) mice displayed severe glomeruli (P < 0.0001) and tubulointerstitial lesions (P < 0.001) compared to kidneys from WT mice. An important finding was the presence of severe glomerulosclerosis in α7(-/-) mice in this early phase of the disease. Kidneys of α7(-/-) mice showed greater accumulation of inflammatory cells and higher expression of chemokines and cytokines than did those of WT mice. In addition, in α7(-/-) fibrotic kidneys, the expression of fibrin, collagen, TGF-β, and tissue inhibitor of metalloproteinase (TIMP)-2 increased, and the expression of TIMP3 declined. The increase in counterregulatory responses to inflammation in α7(-/-) nephritic kidneys did not compensate for the lack of α7nAChR. These findings indicate that α7nAChR plays a key role in regulating the inflammatory response in anti-GBM GN and that disruption of the endogenous protective α7nAChR amplifies inflammation to accelerate kidney damage and fibrosis. Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Collagen; Cytokines; Disease Models, Animal; Female; Fibrin; Fibrosis; Glomerular Basement Membrane; Glomerulonephritis; Inflammation; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Protein Subunits; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-3; Transforming Growth Factor beta | 2015 |
An internal thioester in a pathogen surface protein mediates covalent host binding.
To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a 'chemical harpoon'. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions. Topics: Adhesins, Bacterial; Carrier Proteins; Escherichia coli; Fibrin; Fibrinogen; Humans; Inflammation; Membrane Proteins | 2015 |
Retinoic acid inhibits tissue factor and HMGB1 via modulation of AMPK activity in TNF-α activated endothelial cells and LPS-injected mice.
Retinoic acid (RA) is the active vitamin A derivative and has diverse immunomodulatory actions. We hypothesized that RA reduces prothrombotic mediators such as tissue factor (TF) in endothelial cells during inflammatory conditions via an AMPK-dependent pathway, which attenuates cardiovascular complications.. RA significantly increased AMPK and Akt phosphorylation in a time- and concentration-dependent manner in endothelial cells (EC). RA downregulated TF expression at the transcriptional and translational levels in TNF-α activated ECs, which was reversed by the silencing of AMPK and transfection of DN-AMPK. Interestingly, the PI3-kinase inhibitor LY294002 reversed the RA effect on TF expression. Increased AMPK phosphorylation by RA was inhibited by LY294002. However, increased Akt phosphorylation was not reduced by compound C, indicating that PI3K/Akt signaling modulates AMPK activity. In addition, RA reduced HMGB1 release in TNF-α activated ECs, which was reversed by both LY294001 and siAMPK. Importantly, administration of RA (1 mg/kg) significantly reduced blood TF activity, circulating HMGB1 and PAI-1 levels and expression of hepatic TF mRNA as well as fibrin deposition in LPS (5 mg/kg)-injected mice.. Taken together, the activation of PI3K/Akt by RA modulates AMPK activity in ECs and plays a crucial role in the inhibition of coagulatory factors such as TF, PAI-1, and HMGB1 in inflammatory conditions. Topics: AMP-Activated Protein Kinases; Animals; Chromones; Culture Media; Endothelial Cells; Fibrin; HMGB1 Protein; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred BALB C; Morpholines; Phosphatidylinositol 3-Kinases; Phosphorylation; Plasminogen Activator Inhibitor 1; Serpin E2; Thromboplastin; Tretinoin; Tumor Necrosis Factor-alpha | 2015 |
Use of a fibrin-based system for enhancing angiogenesis and modulating inflammation in the treatment of hyperglycemic wounds.
The complex pathophysiology of chronic ulceration in diabetic patients is poorly understood; diabetes-related lower limb amputation is a major health issue, which has limited effective treatment regimes in the clinic. This study attempted to understand the complex pathology of hyperglycemic wound healing by showing profound changes in gene expression profiles in wounded human keratinocytes in hyperglycemic conditions compared to normal glucose conditions. In the hyper-secretory wound microenvironment of hyperglycemia, Rab18, a secretory control molecule, was found to be significantly downregulated. Using a biomaterial platform for dual therapy targeting the two distinct pathways, this study aimed to resolve the major dysregulated pathways in hyperglycemic wound healing. To complement Rab18, and promote angiogenesis eNOS was also targeted, and this novel Rab18-eNOS therapy via a dynamically controlled 'fibrin-in-fibrin' delivery system, demonstrated enhanced wound closure, by increasing functional angiogenesis and reducing inflammation, in an alloxan-induced hyperglycemic preclinical ear ulcer model of compromised wound healing. Topics: Animals; Cell Proliferation; Fibrin; Humans; Hyperglycemia; Immunohistochemistry; Inflammation; Keratinocytes; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; rab GTP-Binding Proteins; Rabbits; Wound Healing | 2014 |
Plasmin deficiency leads to fibrin accumulation and a compromised inflammatory response in the mouse brain.
Excess fibrin in blood vessels is cleared by plasmin, the key proteolytic enzyme in fibrinolysis. Neurological disorders and head trauma can result in the disruption of the neurovasculature and the entry of fibrin and other blood components into the brain, which may contribute to further neurological dysfunction.. While chronic fibrin deposition is often implicated in neurological disorders, the pathological contributions attributable specifically to fibrin have been difficult to ascertain. An animal model that spontaneously acquires fibrin deposits could allow researchers to better understand the impact of fibrin in neurological disorders.. Brains of plasminogen (plg)- and tissue plasminogen activator (tPA)-deficient mice were examined and characterized with regard to fibrin accumulation, vascular and neuronal health, and inflammation. Furthermore, the inflammatory response following intrahippocampal lipopolysaccharide (LPS) injection was compared between plg(-/-) and wild type (WT) mice.. Both plg(-/-) and tPA(-/-) mice exhibited brain parenchymal fibrin deposits that appear to result from reduced neurovascular integrity. Markers of neuronal health and inflammation were not significantly affected by proximity to the vascular lesions. A compromised neuroinflammatory response was also observed in plg(-/-) compared to WT mice following intrahippocampal LPS injection. These results demonstrate that fibrin does not affect neuronal health in the absence of inflammation and suggest that plasmin may be necessary for a normal neuroinflammatory response in the mouse CNS. Topics: Animals; Astrocytes; Brain; Female; Fibrin; Fibrinolysin; Fibrinolysis; Hippocampus; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Plasminogen; Tissue Plasminogen Activator | 2014 |
Fibrin accumulation secondary to loss of plasmin-mediated fibrinolysis drives inflammatory osteoporosis in mice.
Osteoporosis is a skeletal disorder characterized by low bone mass and increased bone fragility associated with aging, menopause, smoking, obesity, or diabetes. Persistent inflammation has been identified as an instigating factor in progressive bone loss. In addition to the role of fibrin in coagulation, inordinate fibrin deposition within a tissue matrix results in increased local inflammation. Given that fibrin accumulation is a hallmark of osteoporosis-related comorbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis.. Multiple imaging modalities, bone integrity metrics, and histologic analyses were employed to evaluate skeletal derangements in relation to fibrin deposition, circulating fibrinogen levels, and systemic markers of inflammation in mice that were plasminogen deficient and in plasminogen-deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the αM β2 binding motif.. Mice generated with a genetic deficit in the key fibrinolytic protease, plasmin, uniformly developed severe osteoporosis. Furthermore, the development of osteoporosis was fibrin(ogen) dependent, and the derangements in the bone remodeling unit were mechanistically tied to fibrin(ogen)-mediated activation of osteoclasts via activation of the leukocyte integrin receptor αM β2 on monocytes and secondary stimulation of osteoblasts by RANKL. Notably, the genetic elimination of fibrin(ogen) or the expression of a mutant form of fibrinogen retaining clotting function but lacking the αM β2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels.. Taken together, these data reveal for the first time that fibrin promotes inflammation-driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology. Topics: Animals; Fibrin; Fibrinolysin; Fibrinolysis; Inflammation; Male; Mice; Osteoporosis | 2014 |
Etanercept exacerbates inflammation and pathology in a rabbit model of active pulmonary tuberculosis.
Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-α) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-α signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-α antagonist, on the host immune response and pathogenesis in TB. Topics: Animals; Collagen; Disease Models, Animal; Down-Regulation; Etanercept; Fibrin; Granuloma; Inflammation; Lung; Mycobacterium tuberculosis; Rabbits; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha; Up-Regulation | 2014 |
Effect of polymer-free TiO2 stent coated with abciximab or alpha lipoic acid in porcine coronary restenosis model.
Polymer-free drug-eluting stents (DES) may overcome the shortcomings of polymer-based DES. The aim of this study was to examine the effect of the polymer-free TiO2 film-coated stent with abciximab or alpha lipoic acid in a porcine coronary overstretch restenosis model.. Pigs were randomized into four groups in which the coronary arteries (24 pigs, 48 coronaries in each group) had TiO2 film-coated stent with abciximab (TCA, n = 12), TiO2 film-coated stent with alpha lipoic acid (TCALA, n = 12), biolimus A9-eluting stents with biodegradable polymer (BES, n = 12), and TiO2 film-coated stent (TCstent, n = 12). Histopathologic analysis was performed at 28 days after stenting.. There was no significant difference in the injury score and internal elastic lamina (IEL) among the four groups. There were significant differences in the lumen area, neointima area, percent area stenosis, fibrin score, and inflammation score among the four groups [2.7 ± 1.0mm(2), 2.6 ± 0.94 mm(2), 48.9 ± 16.25%, 1.0 (range 0.0-3.0), 1.0 (range 0.0-2.0) in TCA stent group vs. 2.7 ± 1.24 mm(2), 2.9 ± 0.83 mm(2), 53.5 ± 17.19%, 1.0 (range 0.0-2.0), 1.0 (range 0.0-2.0) in TCALA stent group vs. 2.7 ± 1.30 mm(2), 2.6 ± 1.06 mm(2), 50.1 ± 23.20%, 2.0 (range 1.0-3.0), 2.0 (range 1.0-3.0) in BES group vs. 1.7 ± 0.63 mm(2), 3.3 ± 0.58 mm(2), 60.2 ± 10.12%, 0.5 (range 0.0-2.0), 1.0 (range 0.0-2.0) in TC stent group, respectively].. TCA and TCALA are more effective to reduce neointimal hyperplasia compared to TC. Moreover, fibrin and inflammation scores are significantly lower in TCA and TCALA than BES in porcine coronary restenosis model. Topics: Abciximab; Animals; Antibodies, Monoclonal; Coronary Restenosis; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Hyperplasia; Immunoglobulin Fab Fragments; Inflammation; Male; Neointima; Percutaneous Coronary Intervention; Polymers; Swine; Thioctic Acid; Time Factors; Titanium; Treatment Outcome | 2014 |
Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques.
Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques.. Atherosclerotic plaques in the carotid arteries of Apoe(-/-) mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (P<0.05) in factor XI antisense oligonucleotide-treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense-treated animals. No neutrophils were present.. Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense-treated animals show a less severe inflammatory response. Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Coagulation; Blood Platelets; Carotid Arteries; Carotid Artery Diseases; Cholesterol, Dietary; Collagen; Disease Models, Animal; Factor XI; Fibrin; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotides, Antisense; Plaque, Atherosclerotic; Platelet Adhesiveness; Platelet Aggregation; Rupture, Spontaneous; Thrombosis; Time Factors | 2014 |
Peri-strut low-intensity areas in optical coherence tomography correlate with peri-strut inflammation and neointimal proliferation: an in-vivo correlation study in the familial hypercholesterolemic coronary swine model of in-stent restenosis.
Peri-strut low-intensity area (PLI) is a common imaging finding during the evaluation of in-stent neointima using optical coherence tomography (OCT). We aimed to determine the biological significance of PLI by comparing in-vivo OCT images with the corresponding histological sections obtained from the familial hypercholesterolemic swine model of coronary stenosis.. A total of 26 coronary vessels of nine familial hypercholesterolemic swine were injured with 30% balloon overstretch and then immediately followed by everolimus eluting or bare metal stent placement at 20% overstretch. At 30 days, all stented vessels were subjected to in-vivo OCT analysis and were harvested for histological evaluation. For OCT analysis, stent cross-sections (three per stent) were categorized into presence (PLI+) or absence (PLI-) of PLI. In histology, inflammation and fibrin deposition were scored semiquantitatively from 0 (none) to 3 (severe).. PLI was found in 64.9% of stent sections. Peri-strut inflammation was more frequently observed in OCT sections PLI (+) compared with PLI (-) (56.0 vs. 7.4%, P=0.01). In contrast, peri-strut fibrin deposits was similar in both groups (PLI+=58.0% vs. PLI-=59.3%, P=0.94). Histological neointimal thickness was significantly higher in PLI (+) sections (mean±SE: 0.68±0.06 vs. 0.34±0.02 mm; P<0.01), yielding a higher percent area stenosis compared with PLI (-) (mean±SE: 59.0±4.4 vs. 34.1±2.2%, P<0.01). The PLI diagnostic sensitivity and specificity for inflammation were 80 and 76.1%, respectively (>56% PLI, area under the curve=0.86, P<0.01), whereas for fibrin deposition, the sensitivity and specificity were 42.2 and 76.1%, respectively (area under the curve=0.56, P=NS). Area under the receiver operating characteristic curve was significantly higher for identifying inflammation than fibrin (0.86 vs. 0.56, P<0.01). The severity of PLI correlated with the neointimal thickness when assessed by OCT (R=0.79, P<0.001).. The presence of PLI in OCT correlates with neointimal thickness and appears to have a diagnostic value in the recognition of peri-strut inflammation, therefore possibly serving as a surrogate for in-vivo assessment of stent efficacy. Topics: Animals; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Graft Occlusion, Vascular; Hyperlipoproteinemia Type II; Hyperplasia; Inflammation; Male; Neointima; Stents; Swine; Tomography, Optical Coherence | 2014 |
Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice.
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. Robust coagulation cascade activation is common in obese patients with NAFLD. We identified a critical temporal relationship between thrombin generation and the manifestation of hepatic steatosis, inflammation, and injury in C57BL/6J mice fed a high-fat diet (HFD) for 1, 2, and 3 months. Mice fed a HFD exhibited dramatic increases in hepatocellular injury and inflammation over time. Hepatic fibrin deposition preceded an increase in serum alanine aminotransferase, and the most dramatic changes in liver histopathology occurred in conjunction with a detectable increase in plasma thrombin-antithrombin levels at 3 months. To directly determine whether thrombin activity promotes NAFLD pathogenesis, mice were fed a HFD and simultaneously treated with the direct thrombin inhibitor dabigatran etexilate for 3 months. Notably, dabigatran treatment significantly reduced hepatic fibrin deposition, hepatic inflammation, hepatocellular injury, and steatosis in mice fed a HFD. Of interest, dabigatran treatment also significantly attenuated HFD-induced body weight gain. Gene expression analysis suggested that thrombin potentially drives NAFLD pathogenesis by altering the expression of genes associated with lipid metabolism and bile acid synthesis. Collectively, the results suggest that thrombin activity is central to HFD-induced body weight gain, liver injury, and inflammation and provide the proof-of-principle evidence that pharmacological thrombin inhibition could be effective in limiting NAFLD and associated pathologies. Topics: Alanine Transaminase; Animals; Benzimidazoles; beta-Alanine; Bile Acids and Salts; Dabigatran; Diet, High-Fat; Fatty Liver; Fibrin; Gene Expression; Inflammation; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Thrombin; Weight Gain | 2014 |
Macrophage embedded fibrin gels: an in vitro platform for assessing inflammation effects on implantable glucose sensors.
The erroneous and unpredictable behavior of percutaneous glucose sensors just days following implantation has limited their clinical utility for diabetes management. Recent research has implicated the presence of adherent inflammatory cells as the key mitigating factor limiting sensor functionality in this period of days post-implantation. Here we present a novel in vitro platform to mimic the cell-embedded provisional matrix that forms adjacent to the sensor immediately after implantation for the focused investigation of the effects of early stage tissue response on sensor function. This biomimetic surrogate is formed by imbibing fibrin-based gels with physiological densities of inflammatory RAW 264.7 macrophages. When surrounding functional sensors, macrophage-embedded fibrin gels contribute to sensor signal declines that are similar in both shape and magnitude to those observed in previous whole blood and small animal studies. Signal decline in the presence of gels is both metabolically-mediated and sensitive to cell type and activation. Computational modeling of the experimental setup is also presented to validate the design by showing that the cellular glucose uptake parameters necessary to achieve such experimental declines align well with literature values. Together, these data suggest this in vitro provisional matrix surrogate may serve as an effective screening tool for testing the biocompatibility of future glucose sensor designs. Topics: 3T3 Cells; Animals; Biocompatible Materials; Biosensing Techniques; Blood Glucose; Cell Line; Cells, Immobilized; Fibrin; Gels; Inflammation; Macrophages; Mice; Prostheses and Implants | 2014 |
Coronary thrombus composition: links with inflammation, platelet and endothelial markers.
We investigated whether markers of platelet, neutrophil and endothelial activation, plasma fibrin clot properties and patient clinical profile may characterize coronary thrombus composition in ST-segment elevation myocardial infarction (STEMI) patients.. A total of 40 intracoronary thrombi obtained 4.0-16.5 h since chest pain onset by manual aspiration during primary coronary intervention (PCI) were assessed using scanning electron microscopy. Plasma fibrin clot permeation coefficient (Ks) and clot lysis time (CLT), together with platelet and endothelial activation, fibrinolysis, and inflammation markers, were measured ex vivo in 16 patients on admission (pre-PCI group) and on the next morning in 24 patients (post-PCI group).. Fibrin, erythrocyte, platelet and white blood cell content in the thrombi were estimated at 49.1%, 24.2%, 11.6% and 3.7% respectively. In the pre-PCI group, in addition to fibrinogen, P-selectin and plasminogen activator inhibitor-1 were positively correlated with thrombus fibrin content. In the post-PCI group, in addition to von Willebrand factor antigen (vWF:Ag), soluble CD40 ligand and myeloperoxidase (MPO) were positively correlated with thrombus fibrin content. After adjustment for fibrinogen and onset-to-thrombectomy time circulating vWF:Ag in both groups, and MPO and P-selectin in the pre-PCI group were the independent predictors of fibrin-rich intracoronary thrombus presence. Other predictors were renal impairment, arterial hypertension and time from symptom onset to thrombus aspiration in all patients.. In STEMI patients coronary thrombus composition is partly characterized by plasma markers of platelet, neutrophil and endothelial activation, with a varying contribution of these factors over time. Topics: Acute Disease; Aged; Blood Coagulation; Blood Platelets; Coronary Vessels; Endothelial Cells; Endothelium, Vascular; Female; Fibrin; Fibrinogen; Humans; Inflammation; Male; Microscopy, Electron, Scanning; Middle Aged; Neutrophils; P-Selectin; Percutaneous Coronary Intervention; Plasminogen Activator Inhibitor 1; Platelet Activation; Prospective Studies; Thrombosis; Treatment Outcome | 2014 |
C-reactive protein and fibrin clot strength measured by thrombelastography after coronary stenting.
Inflammation is implicated in the progression of coronary artery disease and the molecular processes of inflammation and thrombosis are closely intertwined. Elevated levels of C-reactive protein (CRP) have been associated with an elevated risk of adverse ischaemic events after coronary stenting and hypercoagulability. Heightened whole blood clot strength measured by thrombelastography (TEG) has been associated with adverse ischaemic events after stenting. We intended to examine the relationship of CRP to plasma fibrin clot strength in patients after coronary stenting. Plasma fibrin clot strength was measured by TEG in 54 patients 16-24 h after undergoing elective percutaneous coronary intervention (PCI). Coagulation was induced in citrated plasma by addition of kaolin and CaCl2. Plasma levels of CRP and fibrinogen were measured by enzyme-linked immunoassay. Increasing quartiles of CRP were associated with increasing levels of maximal plasma fibrin clot strength measured by TEG (P < 0.001) and increasing BMI (P = 0.04). Patients in the highest quartile of CRP had significantly higher maximal fibrin clot strength (G) than the patients in the lowest quartile (G: 3438 ± 623 vs. 2184 ± 576 dyn/cm, P < 0.0001). Fibrinogen concentration was not significantly different across quartiles of CRP (P = 0.97). Patients with established coronary artery disease undergoing coronary stenting who have elevated CRP after PCI exhibit heightened maximal plasma fibrin clot strength as compared with those with low CRP. Thrombotic risk associated with elevated CRP may be linked to procoagulant changes and high tensile fibrin clot strength independent of fibrinogen concentration. Topics: Aged; Angioplasty, Balloon, Coronary; Blood Coagulation; C-Reactive Protein; Calcium Chloride; Coronary Artery Disease; Female; Fibrin; Fibrinogen; Humans; Inflammation; Kaolin; Male; Middle Aged; Risk Factors; Stents; Thrombelastography; Thrombophilia; Thrombosis | 2013 |
Plasminogen controls inflammation and pathogenesis of influenza virus infections via fibrinolysis.
Detrimental inflammation of the lungs is a hallmark of severe influenza virus infections. Endothelial cells are the source of cytokine amplification, although mechanisms underlying this process are unknown. Here, using combined pharmacological and gene-deletion approaches, we show that plasminogen controls lung inflammation and pathogenesis of infections with influenza A/PR/8/34, highly pathogenic H5N1 and 2009 pandemic H1N1 viruses. Reduction of virus replication was not responsible for the observed effect. However, pharmacological depletion of fibrinogen, the main target of plasminogen reversed disease resistance of plasminogen-deficient mice or mice treated with an inhibitor of plasminogen-mediated fibrinolysis. Therefore, plasminogen contributes to the deleterious inflammation of the lungs and local fibrin clot formation may be implicated in host defense against influenza virus infections. Our studies suggest that the hemostatic system might be explored for novel treatments against influenza. Topics: Animals; Antiviral Agents; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Host-Pathogen Interactions; Inflammation; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthomyxoviridae Infections; Plasminogen; Pneumonia, Viral; Virus Replication | 2013 |
Succinobucol-eluting stents increase neointimal thickening and peri-strut inflammation in a porcine coronary model.
The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model.. Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties.. Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES), or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS).. The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days); 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES, and 0.36 ± 0.17 mm for SucRES (P < 0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (P < 0.05), whereas RES reduced inflammation compared with BMS (P < 0.05).. In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting. Topics: Animals; Cardiovascular Agents; Cattle; Cell Survival; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Eluting Stents; Endothelial Cells; Fibrin; Inflammation; Male; Metals; Models, Animal; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Percutaneous Coronary Intervention; Probucol; Prosthesis Design; Sirolimus; Swine | 2013 |
A potential role for plasma uric acid in the endothelial pathology of Plasmodium falciparum malaria.
Inflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, 'parasite-derived' uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria.. We measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5-17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels.. Elevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084). Topics: E-Selectin; Endothelium; Erythrocytes; Fibrin; Humans; Inflammation; Intercellular Adhesion Molecule-1; Malaria, Falciparum; Microvessels; Plasmodium falciparum; Platelet Aggregation; Thrombomodulin; Uric Acid; Vascular Cell Adhesion Molecule-1 | 2013 |
Tumor suppressor APC protein is essential in mucosal repair from colonic inflammation through angiogenesis.
Mucosal repair after acute colonic inflammation is central to maintaining mucosal homeostasis. Failure of mucosal repair often leads to chronic inflammation, sometimes associated with inflammatory bowel disease (IBD). The adenomatous polyposis coli (APC) tumor suppressor gene regulates the Wnt signaling pathway, which is essential for epithelial development, and inactivation of APC facilitates colorectal cancer. Our previous study suggested that APC is involved in pathogenesis of colonic inflammation; however, its role in mucosal repair remains unknown. In this article, we report that colitis induced by dextran sodium sulfate persisted with delayed mucosal repair in Kyoto Apc Delta (KAD) rats lacking the APC C terminus. Defects in the repair process were accompanied by an absence of a fibrin layer covering damaged mucosa and reduced microvessel angiogenesis. APC was up-regulated in vascular endothelial cells (VECs) in inflamed mucosa in KAD and F344 (control) rats. The VECs of KAD rats revealed elevated cell adhesion and low-branched and short-length tube formation. We also found that DLG5, which is associated with IBD pathogenesis, was up-regulated in VECs in inflamed mucosa and interacted with the C terminus of APC. This finding suggests that loss of interaction between the APC C terminus and DLG5 affects VEC morphology and function and leads to persistence of colitis. Therefore, APC is essential for maintenance of intestinal mucosal homeostasis and can consequently contribute to IBD pathogenesis. Topics: Adenomatous Polyposis Coli Protein; Animals; Cell Adhesion; Colitis; Colon; Cytokines; Dextran Sulfate; Endothelial Cells; Epithelium; Fibrin; Inflammation; Inflammation Mediators; Intestinal Mucosa; Male; Membrane Proteins; Microtubule-Associated Proteins; Neovascularization, Physiologic; Protein Binding; Protein Transport; Rats; Rats, Inbred F344; Time Factors; Wnt Signaling Pathway; Wound Healing | 2013 |
Fibrin- and collagen-based matrices attenuate inflammatory and procoagulant responses in human endothelial cell cultures exposed to Staphylococcus aureus.
Infective endocarditis (IE) remains a serious complication after heart valve replacement. Autologous valves constructed by matrix-based tissue engineering are under investigation to increase biocompatibility. The impact of the underlying matrix on the risk to develop IE is not known. The IE is characterized by bacterial adhesion and subsequent interactions of disseminating bacteria with endothelial cells (ECs) and monocytes, evoking endothelial proinflammatory and procoagulant activity, leading to heart valve destruction. In the current study, we, therefore, have seeded human ECs on a fibrin versus collagen gel matrix and, at confluence, infected them with Staphylococcus aureus, Streptococcus sanguis, and Staphylococcus epidermidis. Especially Sta. aureus infected ECs grown on fibrin (4.2% of the inoculum) and collagen (3.7%) matrices, more than on ECs grown on noncoated plates (1.2%; p<0.01). This was associated with higher monocyte adhesion (61%; p<0.01 on fibrin and 43%; p<0.05 on collagen) versus control cultures (30%), even at comparable EC surface expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. The collagen matrix attenuated the Sta. aureus-induced monocyte chemoattractant protein 1 expression 2.0-fold, compared with the noncoated control ECs. This reduction coincided with a 4.2-5.0-fold reduction of the procoagulant activity, triggered in ECs grown on noncoated wells, as a consequence of tissue factor (TF) expression by ECs, further stimulated by EC-bound monocytes. Overall, moderate responses were seen on infection with Str. sanguis and Sta. epidermidis for both gel matrices. Thus, even when fibrin and collagen gel matrices equally increase bacterial adhesion, and subsequent monocyte adhesion to infected ECs, these matrices modulate EC responses to these stimuli, thus resulting in attenuated cytokine production and attenuated adherent monocyte-dependent TF production by the ECs. Further investigations will need to confirm whether also in vivo, EC-matrix interactions can attenuate EC responses to bacteria and inflammatory cells to reduce IE at infected endovascular sites. Topics: Bacterial Adhesion; Blood Coagulation; Cell Adhesion; Cells, Cultured; Collagen; Cytokines; Endothelial Cells; Fibrin; Flow Cytometry; Humans; Inflammation; Monocytes; Staphylococcus aureus; Thromboplastin; Tissue Scaffolds | 2012 |
In vivo comparison of a polymer-free Biolimus A9-eluting stent with a biodegradable polymer-based Biolimus A9 eluting stent and a bare metal stent in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.
To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.. Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry.. The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both).. This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia. Topics: Absorbable Implants; Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Constriction, Pathologic; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Hypercholesterolemia; Hyperplasia; Iliac Artery; Inflammation; Male; Metals; Neointima; Plaque, Atherosclerotic; Polymers; Prosthesis Design; Rabbits; Sirolimus; Stents; Time Factors | 2012 |
Metalloproteinase-mediated Shedding of Integrin β2 promotes macrophage efflux from inflammatory sites.
Macrophage exiting from inflammatory sites is critical to limit the local innate immune response. With tissue insult, resident tissue macrophages rapidly efflux to lymph nodes where they modulate the adaptive immune response, and inflammatory macrophages attracted to the site of injury then exit during the resolution phase. However, the mechanisms that regulate macrophage efflux are poorly understood. This study has investigated soluble forms of integrin β2 whose levels are elevated in experimental peritonitis at times when macrophages are exiting the peritoneum, suggesting that its proteolytic shedding may be involved in macrophage efflux. Both constitutive and inducible metalloproteinase-dependent shedding of integrin β2 from mouse macrophages are demonstrated. Soluble integrin β2 is primarily released as a heterodimeric complex with αM that retains its ability to bind its ligands intracellular adhesion molecule-1, fibrin, and collagen and thus may serve as a soluble antagonist. In a model of accelerated exiting, administration of a metalloproteinase inhibitor prevents macrophage efflux by 50% and impedes loss of macrophage integrin β2 from the cell surface. Exiting of peritoneal macrophages in mice lacking integrin β2 is accelerated, and antibody disruption of integrin β2-substrate interactions can reverse 50% of the metalloprotease inhibitor blockade of macrophage exiting. Thus, our study demonstrates the ability of metalloproteinase-mediated shedding of integrin β2 to promote macrophage efflux from inflammatory sites, and the release of soluble integrin heterodimers may also limit local inflammation. Topics: alpha-Macroglobulins; Animals; CD18 Antigens; Cell Movement; Cells, Cultured; Collagen; Fibrin; Humans; Inflammation; Intercellular Adhesion Molecule-1; Macrophages, Peritoneal; Metalloproteases; Mice; Mice, Mutant Strains; Peritonitis; Protein Multimerization | 2012 |
Bismuth subgallate as a topical haemostatic agent at the palatal wounds: a histologic study in dogs.
This study evaluated the early recovery process of the palatal wounds of dogs using bismuth subgallate. Five healthy adult male dogs underwent eight 5-mm partial-thickness punch biopsies in two paired columns on the palatal mastigatory mucosa. For the haemostasis, one side received moistened gauze pressure (test group 1), and the other received bismuth subgallate (test group 2). A description of the epithelium and connective tissue repair was made at 3, 7, 14 and 21 days. During the first days, a mass of disorganized tissue covered the connective tissue, in which there was intense chronic inflammation, and migration of epithelium cells from the edges towards the central region to close to the wound was seen. The final evaluation demonstrated well organized epithelial and connective tissues in all the samples. Epithelium thickness was measured at 0, 14 and 21 days, from images of the digitalized histological sections. In comparisons between the test groups, the bismuth subgallate group was slightly better than the saline group, but no statistically significant difference was found at 21 days. It was possible to conclude that bismuth subgallate did not interfere in the tissue repair of the palatal mastigatory mucosa in dogs. Topics: Animals; Biopsy, Needle; Bismuth; Blood Coagulation; Cell Movement; Collagen; Connective Tissue; Dogs; Epithelial Cells; Epithelium; Fibrin; Fibroblasts; Gallic Acid; Granulation Tissue; Hemostatics; Image Processing, Computer-Assisted; Inflammation; Keratins; Lymphocytes; Macrophages; Male; Mouth Mucosa; Neutrophils; Organometallic Compounds; Palate; Pressure; Sodium Chloride; Time Factors; Wound Healing | 2012 |
Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor.
In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin α(M)β(2)-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fibγ(390-396A)) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α(M)β(2) binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α(M)β(2) blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-α(M)β(2) interactions may provide a novel strategy for DMD treatment. Topics: Animals; Extracellular Matrix; Fibrin; Fibrinogen; Humans; Inflammation; Leukocytes; Macrophage Activation; Macrophage-1 Antigen; Male; Mice; Mice, Inbred mdx; Mice, Knockout; Mice, Mutant Strains; Models, Biological; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Mutant Proteins; Peptide Fragments; Regeneration; Satellite Cells, Skeletal Muscle | 2012 |
Fibrinoid reaction after lens extraction in rabbit eyes.
To measure the inflammatory reaction in the anterior chamber after lens extraction in a rabbit model and to evaluate the effect of nonsteroidal antiinflammatory drugs (NSAIDs) or steroids on the amount of inflammation as measured by fibrinogen levels in the aqueous humor.. Animal laboratory, Goldschleger Research Institute, Tel Aviv University, Sheba Medical Center, Ramat Gan, Israel.. Experimental study.. Twenty-six eyes of New Zealand white rabbits had lens extraction surgery. One day later, aqueous humor (∼0.1 mL) was withdrawn from the anterior chamber and examined for fibrinogen concentration. Control rabbits received no treatment (9 eyes) or artificial tear eyedrops (5 eyes). One study group received NSAID drops (diclofenac) (6 eyes), and another study group received steroid drops (dexamethasone-neomycin) (6 eyes). All rabbits were treated hourly for 9 applications. Aqueous humor (∼0.1 mL) was withdrawn from the anterior chamber and examined for fibrinogen concentration 1 day later. Fibrinogen levels were also measured in the aqueous in 8 unoperated eyes.. Steroid-treated eyes achieved the lowest inflammatory score, followed by NSAID eyes, artificial tears eyes, and untreated eyes. The mean fibrinogen concentrations in the aqueous humor were 69.1 mg% untreated, 52.0 mg% artificial tears, 18.5 mg% NSAIDs, and 2.8 mg% steroids (P=.002).. Measurement of aqueous fibrinogen after lens extraction surgery in a rabbit animal model was simple and provided a useful parameter for precise evaluation of postoperative intraocular reaction. Steroids and NSAIDs were effective in reducing postoperative inflammation. Steroids reduced inflammation to almost undetectable values.. No author has a financial or proprietary interest in any material or method mentioned. Topics: Acute-Phase Reaction; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aqueous Humor; Cataract Extraction; Dexamethasone; Diclofenac; Fibrin; Fibrinogen; Glucocorticoids; Inflammation; Male; Postoperative Complications; Rabbits | 2012 |
Hemoadsorption reprograms inflammation in experimental gram-negative septic peritonitis: insights from in vivo and in silico studies.
Improper compartmentalization of the inflammatory response leads to systemic inflammation in sepsis. Hemoadsorption (HA) is an emerging approach to modulate sepsis-induced inflammation. We sought to define the effects of HA on inflammatory compartmentalization in Escherichia coli-induced fibrin peritonitis in rats.. HA both reprograms and recompartmentalizes inflammation in sepsis. Sprague Dawley male rats were subjected to E. coli peritonitis and, after 24 h, were randomized to HA or sham treatment (sepsis alone). Venous blood samples collected at 0, 1, 3 and 6 h (that is, 24-30 h of total experimental sepsis), and peritoneal samples collected at 0 and 6 h, were assayed for 14 cytokines along with NO(2)(-/)NO(3)(-). Bacterial counts were assessed in the peritoneal fluid at 0 and 6 h. Plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, CXCL-1, and CCL2 were significantly reduced in HA versus sham. Principal component analysis (PCA) suggested that inflammation in sham was driven by IL-6 and TNF-α, whereas HA-associated inflammation was driven primarily by TNF-α, CXCL-1, IL-10 and CCL2. Whereas -peritoneal bacterial counts, plasma aspartate transaminase levels and peritoneal IL-5, IL-6, IL-18, interferon (IFN)-γ and NO(2)(-)/NO(3)(-) were significantly lower, both CXCL-1 and CCL2 as well as the peritoneal-to-plasma ratios of TNF-α, CXCL-1 and CCL2 were significantly higher in HA versus sham, suggesting that HA-induced inflammatory recompartmentalization leads to the different inflammatory drivers discerned in part by PCA. In conclusion, this study demonstrates the utility of combined in vivo/in silico methods and suggests that HA exerts differential effects on mediator gradients between local and systemic compartments that ultimately benefit the host. Topics: Adsorption; Animals; Biomarkers; Colony Count, Microbial; Computational Biology; Escherichia coli; Fibrin; Hemofiltration; Inflammation; Inflammation Mediators; Liver; Male; Peritoneum; Peritonitis; Principal Component Analysis; Rats; Rats, Sprague-Dawley; Sepsis | 2012 |
Tonsillectomy healing.
We performed a prospective observation study in an outpatient surgical and office setting to compare human post-tonsillectomy healing to human cutaneous wound healing and to established animal models of oral healing.. Fourteen teenaged patients underwent planned tonsillectomy. Intraoral digital photographs were collected at the time of tonsillectomy, during the management of complications, and at postoperative office visits. Serial intraoral photographs of one patient were taken at 48-hour intervals from the time of surgery until postoperative day 17.. Intraoral photographs from the days after tonsillectomy revealed a pattern of inflammation and healing that closely paralleled that in human skin and in canine and porcine oral wound models.. Edema and pain are greatest immediately after surgery, probably as a result of thermal effects and expression of inflammatory mediators that stimulate pharyngeal nociceptors. Pain gradually decreases over time, with an increase in analog pain measures on postoperative days 3 to 5 corresponding to the maximal wound inflammation documented in experimental models. Epithelial ingrowth beneath a fibrin clot begins shortly after wounding. Separation of the fibrin clot about 7 days after surgery exposes vascular stroma. Involution of the vascular stroma and completion of epithelial coverage correlate with decreased pain levels and a lessened risk of bleeding. Topics: Adolescent; Edema; Fibrin; Humans; Inflammation; Neovascularization, Physiologic; Pain Measurement; Photography; Prospective Studies; Respiratory Mucosa; Time Factors; Tonsillectomy; Wound Healing | 2012 |
Bioprinted amniotic fluid-derived stem cells accelerate healing of large skin wounds.
Stem cells obtained from amniotic fluid show high proliferative capacity in culture and multilineage differentiation potential. Because of the lack of significant immunogenicity and the ability of the amniotic fluid-derived stem (AFS) cells to modulate the inflammatory response, we investigated whether they could augment wound healing in a mouse model of skin regeneration. We used bioprinting technology to treat full-thickness skin wounds in nu/nu mice. AFS cells and bone marrow-derived mesenchymal stem cells (MSCs) were resuspended in fibrin-collagen gel and "printed" over the wound site. At days 0, 7, and 14, AFS cell- and MSC-driven wound closure and re-epithelialization were significantly greater than closure and re-epithelialization in wounds treated by fibrin-collagen gel only. Histological examination showed increased microvessel density and capillary diameters in the AFS cell-treated wounds compared with the MSC-treated wounds, whereas the skin treated only with gel showed the lowest amount of microvessels. However, tracking of fluorescently labeled AFS cells and MSCs revealed that the cells remained transiently and did not permanently integrate in the tissue. These observations suggest that the increased wound closure rates and angiogenesis may be due to delivery of secreted trophic factors, rather than direct cell-cell interactions. Accordingly, we performed proteomic analysis, which showed that AFS cells secreted a number of growth factors at concentrations higher than those of MSCs. In parallel, we showed that AFS cell-conditioned media induced endothelial cell migration in vitro. Taken together, our results indicate that bioprinting AFS cells could be an effective treatment for large-scale wounds and burns. Topics: Amniotic Fluid; Animals; Bioprinting; Cell Differentiation; Cell Proliferation; Cells, Cultured; Collagen; Culture Media, Conditioned; Fibrin; Inflammation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Nude; Neovascularization, Physiologic; Re-Epithelialization; Regeneration; Skin; Stem Cells; Wound Healing | 2012 |
Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis.
Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis. Topics: Animals; Blood Coagulation; Cytokines; Disease Models, Animal; Endotoxins; Escherichia coli; Fibrin; Flow Cytometry; Humans; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Peptides; Pseudomonas aeruginosa; Sepsis; Shock, Septic; Thrombin | 2012 |
Glomerular fibrin thrombi in ABO and crossmatch compatible renal allograft biopsies.
Glomerular fibrin thrombi may be an early indication of antibody-mediated rejection in renal allograft biopsies. However, fibrin thrombi have a broad differential; thus, we sought to evaluate the etiology and implications of glomerular fibrin thrombi in allograft biopsies of blood group and cytotoxic crossmatch compatible renal allografts. Biopsies were identified from the pathology files of Oregon Health & Science University. Detailed histopathologic findings were retrospectively correlated with clinical data, treatment, and outcome. Sixteen early posttransplant biopsies had glomerular fibrin thrombi, including three surveillance biopsies. Six of 16 biopsies had no other histopathologic findings; 5/16 had glomerulitis and peritubular capillaritis; 4/16 had concomitant cellular vascular rejection; one had parenchymal infarction. C4d staining was positive in 4/16 cases. Most patients were treated with IVIg and plasmapheresis, others with rapamycin, thymoglobulin, or rituximab. At an average follow-up of 62 months, 8 patients with functioning grafts had a mean serum creatinine of 1.4 mg/dL (122 μmol/L). Antibody-mediated rejection is an important consideration in blood group compatible allograft biopsies with glomerular fibrin thrombi, even with C4d-negative biopsies. However, multidisciplinary evaluation is necessary, given other etiologies, including drug toxicity, hemolytic-uremia syndrome, and large vessel thrombosis. Despite aggressive treatment, both short and long-term graft survival may be compromised. Topics: ABO Blood-Group System; Biopsy; Blood Grouping and Crossmatching; Complement C4b; Fibrin; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppression Therapy; Inflammation; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Peptide Fragments; Thrombosis; Thrombotic Microangiopathies; Time Factors; Transplantation, Homologous; Treatment Outcome | 2011 |
MMP9 is protective against lethal inflammatory mass lesions in the mouse colon.
The family of matrix metalloproteinases (MMPs) is responsible for extracellular matrix degradation during physiological and pathophysiological tissue remodeling processes such as embryogenesis, tissue repair and cancer progression. Despite these important roles of MMPs, inhibition or ablation of individual members of the MMP family in animal models have been shown to have little effect. It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems. We here present genetic data showing that concomitant ablation of MMP9 (gelatinase B) and the serine protease plasmin results in lethal inflammatory mass lesions in the colon. These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells. A time-course study provided evidence that the massive lymphoid hyperplasia and reactive changes were secondary to discrete fibrinous lesions also observed in mice only deficient for plasminogen (Plg), the zymogen for plasmin. These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg. Topics: Alleles; Animals; B-Lymphocytes; Colon; Epithelial Cells; Fibrin; Granulocytes; Inflammation; Leukocyte Count; Lymphocyte Activation; Lymphoid Tissue; Matrix Metalloproteinase 9; Mice; Plasminogen; Protective Agents; Spleen; T-Lymphocytes; Thymus Gland; Wound Healing | 2011 |
Chronic histiocytic intervillositis of unknown etiology: clinical features in a consecutive series of 69 cases.
Chronic histiocytic intervillositis of unknown etiology (CIUE) is a rare placental inflammatory disease, associated with severe obstetric complications. Its pathophysiologic mechanism remains to be elucidated.. To establish anatomical-clinical correlations to improve our understanding of CIUE pathophysiology.. Retrospective study of all cases of CIUE occurring during a 9-year period in a university tertiary hospital center.. CIUE was diagnosed in 69 pregnancies in 50 different women, after early spontaneous abortions (30.4%), late spontaneous abortions (13.0%), in utero deaths (26.1%), and live births (30.4%). Of 39 fetuses surviving to at least 22 weeks, 24 had severe intrauterine growth restriction (61.5%) and 18 died in utero (46.2%). Twelve in utero deaths occurred before 32 weeks of gestation (66.7%). Substantially elevated alkaline phosphatase levels (>600 IU/L) were observed in 55.6% of cases. Microscopic examination of placentas showed that both spontaneous early abortions and intrauterine growth restriction were significantly associated with more intense fibrin deposits.. A diagnosis of CIUE must be considered in cases of severe obstetric complications. We hypothesize that the elevated alkaline phosphatases (ALP) observed during the pregnancy demonstrate the presence of syncytiotrophoblastic lesions due to histiocytosis in the intervillous space, before fibrin deposits cover them. Topics: Abortion, Spontaneous; Adolescent; Adult; Alkaline Phosphatase; Chorionic Villi; Female; Fetal Death; Fetal Growth Retardation; Fibrin; Histiocytes; Histiocytosis; Humans; Inflammation; Placenta Diseases; Pregnancy; Premature Birth; Retrospective Studies | 2011 |
Characterization of cytolytic neutrophil activation in vitro by amorphous hydrated calcium phosphate as a model of biomaterial inflammation.
Calcium ions are utilized in biomolecular biomaterial design for osteomimetic scaffolds and as divalent cross-linking agents, typically for gelation of alginates, stabilisation of protein structure (e.g., fibrinogen) and enzyme activation (e.g., thrombin). Biological interactions with defined calcium phosphates (e.g., hydroxyapatite) are exploited for osteogenesis, although crystalline calcium phosphates (e.g., calcium pyrophosphate) stimulate inflammation. We found that the calcium concentration used in the manufacture of prototype dermal scaffolds made from fibrin/alginate composite was related to the inflammatory infiltration during in vivo integration. In investigating a cause for this inflammatory response, we have identified and characterized a cytolytic inflammatory effect of amorphous calcium phosphate (CaP) formed in physiological solutions, relevant to biomaterial biocompatibility. Isolated human neutrophils (Nφ) were incubated in phosphate-buffered saline with CaCl(2) ranging 2.5-20 mM total calcium. Nφ activation was assessed by morphology and integrin-β2 (CD18a) expression. Mediator release (Nφ-elastase, IL-8, and TNFα) was measured from both Nφ and whole blood cultures plus CaCl(2). CaP exposure increased CD18a expression over 1 h (maximal at 10 mM calcium/ phosphate) with concurrent phagocytosis, cytolysis, and Nφ-elastase release. CaCl(2) induced expression of IL-8 and TNFα in whole blood cultures. These results suggest that CaP formed from the resorption of calcium-containing biomaterials could induce inflammation and accelerate biomaterial degradation, driving further CaP release. This demonstrates a novel mechanism for biomaterial-induced inflammation. The in vitro system described could aid preclinical evaluation of novel biomaterial inflammatory potential. Topics: Alginates; Biocompatible Materials; Buffers; Calcium; Calcium Phosphates; CD18 Antigens; Cytotoxicity, Immunologic; Dermis; Fibrin; Glucuronic Acid; Hexuronic Acids; Humans; Inflammation; Inflammation Mediators; Leukocyte Elastase; Magnesium; Models, Biological; Neutrophil Activation; Neutrophils; Phagocytosis; Phosphates; Spectrometry, X-Ray Emission; Time Factors; Tissue Scaffolds | 2011 |
Fibrinogen deficiency increases liver injury and early growth response-1 (Egr-1) expression in a model of chronic xenobiotic-induced cholestasis.
Chronic cholestatic liver injury induced by cholestasis in rodents is associated with hepatic fibrin deposition, and we found evidence of fibrin deposition in livers of patients with cholestasis. Key components of the fibrinolytic pathway modulate cholestatic liver injury by regulating activation of hepatocyte growth factor. However, the exact role of hepatic fibrin deposition in chronic cholestasis is not known. We tested the hypothesis that fibrinogen (Fbg) deficiency worsens liver injury induced by cholestasis. Fbg-deficient mice (Fbgα(-/-) mice) and heterozygous control mice (Fbgα(+/-) mice) were fed either the control diet or a diet containing 0.025% α-naphthylisothiocyanate (ANIT), which selectively injures bile duct epithelial cells in the liver, for 2 weeks. Hepatic fibrin and collagen deposits were evident in livers of heterozygous control mice fed the ANIT diet. Complete Fbg deficiency was associated with elevated serum bile acids, periportal necrosis, and increased serum alanine aminotransferase activity in mice fed the ANIT diet. Fbg deficiency was associated with enhanced hepatic expression of the transcription factor early growth response-1 (Egr-1) and enhanced induction of genes encoding the Egr-1-regulated proinflammatory chemokines monocyte chemotactic protein-1, KC growth-regulated protein, and macrophage inflammatory protein-2. Interestingly, peribiliary collagen deposition was not evident near necrotic areas in Fbg-deficient mice. The results suggest that in this model of chronic cholestasis, fibrin constrains the release of bile constituents from injured intrahepatic bile ducts, thereby limiting the progression of hepatic inflammation and hepatocellular injury. Topics: 1-Naphthylisothiocyanate; Afibrinogenemia; Aged; Animals; Bile Ducts; Cholestasis; Chronic Disease; Collagen; Diet; Disease Models, Animal; Early Growth Response Protein 1; Feeding Behavior; Female; Fibrin; Fibrinogen; Gene Expression Regulation; Humans; Hyperplasia; Inflammation; Liver; Liver Cirrhosis; Male; Mice; Middle Aged; Neutrophils; Xenobiotics | 2011 |
Is fibrin formation and thrombin generation increased during and after an acute coronary syndrome?
In order to study coagulation and fibrinolysis in acute coronary syndrome (ACS) we used a recently developed assay, called OH-index, which provides simultaneous measurements of fibrin formation and fibrinolysis (fibrin degradation) in the patients' plasma. We also investigated thrombin generation using the calibrated automated thrombogram (CAT), and assessed thrombin generation in vivo by measuring F1+2 plasma concentrations. In addition, to better characterize the patients we also assessed markers of inflammation and endothelial function. Eighty-seven ACS patients were sampled at admission, within 24 hours during treatment with low molecular weight heparin (LMH), and 6 months later; 65 healthy controls were also sampled.. As assessed by OH-index fibrin formation was slightly depressed at admission, profoundly depressed during LMH treatment and comparable to controls at 6 months, whereas fibrin degradation was elevated, particularly during LMH treatment. F1+2 levels decreased during LMH treatment but did not deviate significantly from controls at admission or in convalescence. CAT data showed that peak thrombin was higher at admission and after 6 months compared to controls, whereas the endogenous thrombin potential only tended to be elevated. Both variables were strongly reduced during LMH treatment. Patients had elevated levels of markers of inflammation and endothelial function as expected.. ACS-patients have an increased capacity to generate thrombin and an enhanced capacity to degrade fibrin in the acute phase. Increased thrombin generation persists also 6 months after the event. Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Case-Control Studies; Endothelium, Vascular; Female; Fibrin; Fibrinolysis; Humans; Inflammation; Male; Middle Aged; Thrombin | 2011 |
Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense.
Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII(-/-) mice developed severe signs of pathologic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system. Topics: Animals; Blood Bactericidal Activity; Blood Coagulation; Evolution, Molecular; Factor XIII; Factor XIII Deficiency; Fasciitis, Necrotizing; Fibrin; Fibrinolysin; Humans; Inflammation; Mice; Mice, Inbred CBA; Mice, Knockout; Phylogeny; Species Specificity; Streptococcus pyogenes; Thrombin | 2011 |
Origin of restenosis after drug-eluting stent implantation in hyperglycemia is inflammatory cells and thrombus.
The cellular and molecular mechanisms and safety after drug-eluting stent (DES) implantation in diabetic patients are still poorly understood; therefore, in this study, we evaluated the pathologic responses of the sirolimus-eluting stent (SES) or paclitaxel-eluting stent (PES) in a type I diabetes mellitus (DM) rat model.. The type I DM rat model was manipulated by intra-peritoneal streptozotocin injection. Two weeks later, DES was implanted in the aorta of rats with hyperglycemia or not as a control. Four weeks after DES implantation, the stented aorta was isolated and histomorphometric analysis was performed.. On histomorphometric analysis, increased thrombus, inflammatory cell infiltration, and neointimal hyperplasia (NIH) without change of the smooth muscle cell number after DES implantation were observed in DM rats compared with non-DM (NDM) rats. Furthermore, delayed coverage of mature endothelial cells defined as a von Willebrand factor expression and increased immature endothelial cells as a c-kit expression after DES implantation were observed in DM rats compared with NDM rats. Increased fibrin deposition and decreased hyaluronic acid accumulation at NIH after DES implantation were also observed in DM rats compared with NDM rats.. In conclusion, the main mechanism of restenosis after DES implantation under hyperglycemic conditions was initial thrombus with changes of the extracellular matrix rather than SMC proliferation. These results provided a therapeutic clue for the selection of DES and application of combination therapy using anti-thrombotic and anti-inflammatory drugs in diabetic patients. Topics: Animals; Anti-Inflammatory Agents; Aorta; Body Weight; Coronary Restenosis; Diabetes Mellitus, Type 1; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Humans; Hyaluronic Acid; Hyperglycemia; Inflammation; Male; Paclitaxel; Rats; Rats, Sprague-Dawley; Sirolimus; Thrombosis | 2011 |
Plasmin is essential in preventing periodontitis in mice.
Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue- and urokinase-type plasminogen activators, developed periodontal disease similar to that in Plg-deficient mice; however, mice lacking only tissue- or urokinase-type plasminogen activator remained healthy. Supplementation by injection of Plg-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Plg-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases. Topics: Alkaline Phosphatase; Animals; Disease Models, Animal; Fibrin; Fibrinolysin; Immunohistochemistry; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Genetic; Neutrophils; Periodontal Diseases; Periodontitis; Time Factors | 2011 |
Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments.
The interaction of the fibrin βN-domain with VE-cadherin on endothelial cells is implicated in transendothelial migration of leukocytes, and the β15-42 fragment representing part of this domain has been shown to inhibit this process. However, our previous study revealed that only a dimeric (β15-66)(2) fragment, corresponding to the full-length βN-domain and mimicking its dimeric arrangement in fibrin, bound to VE-cadherin.. To test our hypothesis that dimerization of β15-42-containing fragments increases their affinity for VE-cadherin and ability to inhibit transendothelial migration of leukocytes.. Interaction of β15-42-containing fragments with VE-cadherin was characterized by ELISA and surface plasmon resonance. The inhibitory effect of such fragments was tested in vitro with a leukocyte transendothelial migration assay and in vivo with mouse models of peritonitis and myocardial ischemia-reperfusion injury.. First, we prepared the monomeric β15-42 and β15-64 fragments and their dimeric forms, (β15-44)(2) and (β15-66)(2) , and studied their interaction with the fibrin-binding domain of VE-cadherin, VE-cad(3). The experiments revealed that both dimeric fragments bound to VE-cad(3) with high affinity, whereas the affinities of β15-42 and β15-64 were significantly lower. Next, we tested the ability of these fragments to inhibit leukocyte transmigration in vitro and infiltration into the inflamed peritoneum in vivo, and found that the inhibitory effects of the dimers on these processes were also superior. Furthermore, (β15-44)(2) significantly reduced myocardial injury induced by ischemia-reperfusion.. The results confirm our hypotheses and indicate that (β15-66)(2) and (β15-44)(2) , which exhibited much higher affinity for VE-cadherin, are highly effective in suppressing inflammation by inhibiting leukocyte transmigration. Topics: Animals; Antigens, CD; Cadherins; Cardiotonic Agents; Cell Movement; Dimerization; Endothelial Cells; Fibrin; Fibrin Fibrinogen Degradation Products; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Inflammation; Leukocytes; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Peptide Fragments; Peritonitis; Protein Interaction Domains and Motifs | 2011 |
The cardioprotective effects of marrubiin, a diterpenoid found in Leonotis leonurus extracts.
Leonotis leonurus L. (Lamiaceae) is used as a traditional medicine for a variety of ailments in South Africa. The diterpene marrubiin is the major product constituent in specimens of this plant occurring in South Africa.. Marrubiin isolated from South African specimens of L. leonurus in addition to an organic extract of L. leonurus were tested in vivo, ex vivo and in vitro for their anticoagulant, antiplatelet and anti-inflammatory activities.. Marrubiin and the organic extract suppressed coagulation, platelet aggregation and inflammatory markers. For the coagulation markers it was found that the organic extract and marrubiin significantly prolonged activated partial thromboplastin time (APTT). Fibrin and D-dimer formation were drastically decreased. These findings were observed in an ex vivo model and an obese rat model. Chemokines enhance leukocyte recruitment to inflammatory sites. TNF-α and RANTES secretion were significantly reduced by the extract and marrubiin when determined in the obese rat model relative to the controls. Calcium mobilization and TXB(2) synthesis were suppressed by the extract and marrubiin. An in vitro model was used to elucidate the antiplatelet mechanism and it was found that the extract and marrubiin inhibited platelet aggregation by inhibiting the binding of fibrinogen to glycoprotein (GP) IIb/IIIa receptor in a concentration dependent manner.. The findings reflect that marrubiin largely contributes to the extract's anticoagulant, antiplatelet and anti-inflammatory effects observed. Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Calcium; Chemokine CCL5; Diterpenes; Dose-Response Relationship, Drug; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolytic Agents; Glycoproteins; Inflammation; Lamiaceae; Male; Obesity; Partial Thromboplastin Time; Phytotherapy; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thromboxanes; Tumor Necrosis Factor-alpha | 2011 |
Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice.
Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations. Topics: Animals; Arsenites; Chemical and Drug Induced Liver Injury; Dietary Fats; Disease Models, Animal; Extracellular Matrix; Fatty Liver; Fibrin; Inflammation; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Risk Factors; Sodium Compounds; Weight Gain | 2011 |
Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study.
The objective of the study was to determine the relation of platelet reactivity, hypercoagulability and inflammation in various stages of coronary artery disease acuity (CAD). Thrombin-induced platelet-fibrin clot strength (MA), time to initial platelet-fibrin clot formation (R), C-reactive protein (CRP), prothrombotic factors, activated GPIIb/IIIa receptor expression and other biomarkers were studied in patients with asymptomatic stable CAD (AS), in patients undergoing PCI for stable (SA) and unstable angina (UA). MA and R were measured by thrombelastography, GPIIb/IIIa expression by flow cytometry and all other markers by fluorokine multianalyte profiling assays. An overall increase in all measurements from a clinically stable to an unstable disease state was observed. There was a distinct stepwise increment in MA [AS vs. SA (p = 0.02), SA vs. UA (p = 0.02) and AS vs. UA (p < 0.001)]. MA exhibited the strongest correlation with other prothrombotic markers (p < or = 0.02), with CRP (p < 0.001) at all levels of CAD acuity. A distinct pathophysiological state of heightened platelet function, hypercoagulability and inflammation marks the presence of unstable cardiovascular disease requiring intervention. Further studies are required to investigate the primary mechanisms linking the above processes associated with a prothrombotic state resulting in clinical destabilization of the disease. Topics: Aged; Biomarkers; Blood Platelets; C-Reactive Protein; Cohort Studies; Coronary Artery Disease; Disease Progression; Female; Fibrin; Flow Cytometry; Humans; Inflammation; Male; Thrombelastography; Thrombophilia | 2010 |
Polymer-free biolimus a9-coated stent demonstrates more sustained intimal inhibition, improved healing, and reduced inflammation compared with a polymer-coated sirolimus-eluting cypher stent in a porcine model.
Drug-eluting stents effectively reduce restenosis but may increase late thrombosis and delayed restenosis. Persistent polymer, the drug, or a combination of both could be responsible. Local delivery of Biolimus A9, a rapamycin derivative, from a polymer-free BioFreedom stent (Biosensors International) may prevent these complications.. We compared high-dose (HD) (225 microg/14 mm Biolimus A9) and low-dose (LD) (112 microg/14 mm Biolimus A9) BioFreedom stents with a polymer-coated sirolimus-eluting Cypher stent (SES) and a bare-metal stent (BMS) at 28 days and 180 days in an overstretch coronary mini-swine model with histomorphometric and histological analysis. At 28 days, there was a reduction in neointimal proliferation by HD, LD, and SES compared with BMS (neointimal thickness: HD, 0.080+/-0.032; LD, 0.085+/-0.038; SES, 0.064+/-0.037; BMS, 0.19+/-0.111 mm; P<0.001; BMS > HD/LD/SES). At 180 days, both BioFreedom stents were associated with reduced neointimal proliferation, whereas SES exhibited increased neointima (neointimal thickness: HD, 0.12+/-0.034; LD, 0.10+/-0.040; SES, 0.20+/-0.111; BMS, 0.17+/-0.099 mm; P<0.001; SES > HD/LD; BMS > LD). At 180 days, BioFreedom stents showed decreased fibrin and inflammation, including granuloma and giant cells, compared with SES.. The polymer-free Biolimus A9-coated stent demonstrates equivalent early and superior late reduction of intimal proliferation compared with SES in a porcine model. After implantation of BioFreedom stent, delayed arterial healing was minimal, and there was no increased inflammation at 180 days compared with SES implantation. The use of polymer-free stents may have a potential long-term benefit over traditional polymeric-coated drug-eluting stents. Topics: Animals; Cell Proliferation; Coronary Restenosis; Drug-Eluting Stents; Fibrin; Giant Cells; Granuloma; Inflammation; Sirolimus; Swine; Swine, Miniature; Tunica Intima; Wound Healing | 2010 |
Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation.
The urokinase plasminogen activator receptor (uPAR) has emerged as a potential regulator of cell adhesion, cell migration, proliferation, differentiation, and cell survival in multiple physiologic and pathologic contexts. The urokinase plasminogen activator (uPA) was the first identified ligand for uPAR, but elucidation of the specific functions of the uPA-uPAR interaction in vivo has been difficult because uPA has important physiologic functions that are independent of binding to uPAR and because uPAR engages multiple ligands. Here, we developed a new mouse strain (Plau(GFDhu/GFDhu)) in which the interaction between endogenous uPA and uPAR is selectively abrogated, whereas other functions of both the protease and its receptor are retained. Specifically, we introduced 4 amino acid substitutions into the growth factor domain (GFD) of uPA that abrogate uPAR binding while preserving the overall structure of the domain. Analysis of Plau(GFDhu/GFDhu) mice revealed an unanticipated role of the uPA-uPAR interaction in suppressing inflammation secondary to fibrin deposition. In contrast, leukocyte recruitment and tissue regeneration were unaffected by the loss of uPA binding to uPAR. This study identifies a principal in vivo role of the uPA-uPAR interaction in cell-associated fibrinolysis critical for suppression of fibrin accumulation and fibrin-associated inflammation and provides a valuable model for further exploration of this multifunctional receptor. Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Disease Models, Animal; Female; Fibrin; Flow Cytometry; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Inflammation; Liver; Lung Injury; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Pneumonia; Receptors, Urokinase Plasminogen Activator; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin Diseases; Survival Rate; Urokinase-Type Plasminogen Activator; Wound Healing | 2010 |
Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis.
Altered fibrin clot properties have been reported in cardiovascular diseases (CVD) and inflammatory states. Given increased prevalence of CVD in patients with rheumatoid arthritis (RA), we investigated whether fibrin characteristics are also altered in RA patients.. We studied 46 consecutive RA patients versus 50 controls matched for age and gender. Ex vivo plasma clot permeability, turbidity, tissue-type plasminogen activator (tPA)-induced fibrinolysis, and scanning electron microscopy (SEM) images of clots were evaluated.. Patients with RA had lower clot permeability, faster clot formation, higher maximum clot absorbency indicating thicker fibrin fibers, maximum clot mass and prolonged fibrinolysis time than controls. Maximum rates of clot lysis were similar in both groups. SEM images showed formation of dense clots with many projections on fibrin fibers. Clot permeability inversely correlated with fibrinogen, tPA, plasminogen activator inhibitor-1 (PAI-1), CRP, platelet count, disease activity score (DAS28) and a marker of oxidative stress, 8-iso-prostaglandin F2alpha (r from -0.44 to -0.79; all, p<0.0001). Similar positive associations were found for clot lysis time (r 0.44 to 0.69; all, p<0.01). Multiple regression analysis showed that fibrinogen was the only independent predictor of clot permeability (R2=0.87, p<0.0001) and lysis time (R2=0.80, p<0.003) in RA. Maximum D-dimer levels released from clots, maximum clot turbidity and the time of clot formation were predicted by PAI-1 (all, p<0.05).. We showed unfavorably altered plasma fibrin clot structure and function in RA, which might contribute to an increased risk of thrombotic events in this disease. Topics: Adult; Aged; Blood Coagulation Tests; Cardiovascular Diseases; Case-Control Studies; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Inflammation; Male; Middle Aged; Permeability; Plasminogen Activator Inhibitor 1; Thrombosis; Tissue Plasminogen Activator; Young Adult | 2010 |
Left atrial appendage obliteration: mechanisms of healing and intracardiac integration.
The objectives of this study were: 1) to delineate the temporal course of histopathologic healing as the left atrial appendage (LAA) is obliterated by a mechanical device; and 2) to compare this process with other intravascular and intracardiac implanted technologies.. Intracardiac device healing is incompletely understood. We thus studied the histopathology of device-based LAA obliteration.. Nine dog hearts were examined over time after LAA device placement and results were compared with human hearts with prior LAA obliteration using the same device.. At 3 days in dogs, atrial surfaces were covered by fibrin, which sealed gaps between the LA wall and the device and filled the LA appendage cavity. At 45 days, endothelial cells covered the endocardial surface with underlying smooth muscle cells that sealed the device-LA interface. Regions with prior thrombus were replaced by endocardium surrounding the device membrane. Disorganized thrombus remained in the LAA body and at the periphery near the appendage walls. Mild inflammation was observed as thrombus resorbed. By 90 days, a complete endocardial lining covered the former LAA ostium. Organizing thrombus had become connective tissue, with no residual inflammation. The human necropsy hearts had similar findings. In these 4 hearts (139, 200, 480, and 852 days after implant), the ostial fabric membrane was covered with endocardium. The appendage surface contained organizing thrombus with minimal inflammation. Organizing fibrous tissue was inside the LAA cavity, prominent near the atrial wall. The LAA interior contained organizing thrombus.. This intracardiac device integration study delineated healing stages of early thrombus deposition, thrombus organization, inflammation and granulation tissue, final healing by connective tissue, and endocardialization without inflammation. These observations may yield insight into cellular healing processes in other cardiac devices. Topics: Animals; Atrial Appendage; Cardiac Surgical Procedures; Dogs; Endocardium; Endothelial Cells; Fibrin; Granulation Tissue; Humans; Inflammation; Myocytes, Smooth Muscle; Prosthesis Design; Thoracotomy; Thrombosis; Time Factors; Wound Healing | 2010 |
Rice body mass formation mimicking a neoplastic disease around the trochanteric bursae of the hip.
Multiple rice body formation is an uncommon inflammatory process. Sometimes it leads to a big mass in unusual locations. Although sometimes associated with bursitis and systemic diseases, such as rheumatoid arthritis, the pathophysiology of this rare entity is still obscure. We present a 29-year-old woman with multiple rice body mass formation in the trochanteric bursa of the left hip. She was operated, and had no recurrence at 18 months after the surgery. Topics: Adult; Bursa, Synovial; Bursitis; Collagen; Female; Fibrin; Hip Joint; Humans; Immunohistochemistry; Inflammation; Magnetic Resonance Imaging; Soft Tissue Neoplasms; Suction; Synovial Membrane | 2010 |
The link between heightened thrombogenicity and inflammation: pre-procedure characterization of the patient at high risk for recurrent events after stenting.
Heightened thrombogenicity and biomarker evidence of inflammation have been independently associated with ischemic risk in patients with coronary artery disease. However, a study examining their relation has not been reported. We analysed the relation between measurements of thrombogenicity and biomarkers in patients undergoing stenting and followed for 24 months recurrent ischemic events. In 84 consecutive patients undergoing stenting, pre-procedure thrombogenicity was measured by thrombelastography (TEG) and conventional aggregometry whereas biomarkers were measured by fluorokine multi-analyte profiling. Patients were stratified into quartiles based on platelet-fibrin clot strength (MA) by TEG and correlated with ischemic event occurrence. Patients in the highest MA quartile (high MA) had greater ADP-induced platelet aggregation (57.5 +/- 15.0% vs. 47.9 +/- 17.6%, p = 0.05), C-reactive protein (25.0 +/- 5.6 vs. 4.2 +/- 1.0 microg/mL, p = 0.006) and interleukin-8 (23.8 +/- 2.8 vs. 14.1 +/- 1.6 pg/mL, p < 0.001) than patients within the lowest MA quartile (low MA). Epidermal growth factor (7.7 +/- 2.2 vs. 1.2 +/- 0.3 pg/mL, p = 0.006) and vascular endothelial growth factor (296 +/- 35 vs. 190 +/- 10 pg/mL, p = 0.05) were also higher. Patients with high-MA had an ischemic event more often than patients with low-MA (48% vs. 13%, p = 0.02). Our study suggests that a link is present between inflammation and heightened thrombogenicity measured pre-procedurally in the patient at high risk for recurrent ischemic events after stenting. Larger studies are required to solidify these observations and their clinical relevance. Topics: Aged; Aged, 80 and over; Biomarkers; Fibrin; Humans; Inflammation; Kaplan-Meier Estimate; Male; Middle Aged; Platelet Aggregation; Platelet Function Tests; Recurrence; Risk Factors; Stents; Thrombelastography; Thrombin; Thrombosis | 2009 |
Protease-activated receptor 2 blocking peptide counteracts endotoxin-induced inflammation and coagulation and ameliorates renal fibrin deposition in a rat model of acute renal failure.
Glomerular and microvascular thrombosis due to the activation of inflammation and coagulation pathway contribute to the occurrence of acute renal failure in sepsis. The protease-activated receptors (PARs) have been shown to play an important role in the interplay between inflammation and coagulation. We hypothesized that PAR-2 blocking would improve glomerular and vascular thrombosis by attenuating inflammation and coagulation, leading to the prevention of acute renal failure, and assessed the effects of the PAR-2 blocking peptide (PAR-2 BP) in a rat model of LPS-induced acute renal failure. Levels of TNF-alpha were significantly expressed 1 h after LPS administration, followed by 1) an increase in levels of tissue factor, factor VIIa, factor Xa, thrombin and plasminogen activator inhibitor 1; 2) unchanged levels of tissue factor pathway inhibitor; and 3) subsequent deposition of fibrin in kidney tissues, which led to the elevation of creatinine and blood urea nitrogen. Time-dependent PAR-2 expression was observed at both the gene and protein levels. Immunoreactivities of PAR-2 and fibrin were observed in the glomerulus and small arteries. Protease-activated receptor blocking peptide suppressed TNF-alpha elevation and attenuated activation of the coagulation, thus leading to a decrease in fibrin formation and its deposition in the glomerulus. However, the levels of creatinine and blood urea nitrogen remained unchanged. These results show that PAR-2 plays a key role in the inflammatory and coagulation process of LPS-induced renal failure; however, PAR-2 inhibition alone does not affect improvement in the renal function. Topics: Acute Kidney Injury; Animals; Blood Coagulation; Blood Urea Nitrogen; Disease Models, Animal; Endotoxins; Fibrin; Inflammation; Lipopolysaccharides; Male; Rats; Rats, Wistar; Receptor, PAR-2; Time Factors | 2009 |
Coronary arteries angiogenesis in ischemic myocardium: biocompatibility and biodegradability of various hydrogels.
To evaluate the biocompatibility and biodegradability of various hydrogels and choose suitable hydrogels for the coronary arteries angiogenesis in ischemic myocardium, we synthesized six kinds of hyaluronan hydrogels, fibrin hydrogel, poly(vinyl alcohol)-chitosan hydrogel, and obtained elastin hydrogels. We examined their degradation rates and cytotoxicity in vitro. Then, hydrogels were implanted into rat adductor muscles for 1, 2, or 4 weeks. Hydrogels and surrounding tissues were resected, followed by hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemical staining for measurements of degradation, immune response, and angiogenesis. 2-Iminothiolane grafted hyaluronan hydrogel and periodate oxidated hyaluronan hydrogel presented rapid degradation rates, low quantity of inflammation-mediating cells (12 +/- 3 and 12 +/- 4 per 2.5 x 10(-3) mm(2), respectively, at week 2), thin fibrous capsules (scores were 3.8 +/- 0.1 and 4.0 +/- 0.3 per 0.33 mm(2), respectively, at week 2) with dense blood vessels in the areas surrounding the implanted hydrogels. 2-Iminothiolane grafted hyaluronan and periodate oxidated hyaluronan hydrogels with appropriate degradation rates and low immune responses were suitable for coronary arteries angiogenesis in ischemic myocardium. Topics: Animals; Biocompatible Materials; Cells, Cultured; Chitosan; Coronary Vessels; Drug Carriers; Elastin; Fibrin; Gene Transfer Techniques; Hyaluronic Acid; Hydrogels; Inflammation; Male; Materials Testing; Muscle, Skeletal; Muscle, Smooth, Vascular; Myocardial Ischemia; Neovascularization, Physiologic; Pilot Projects; Polymers; Polyvinyls; Rats; Rats, Sprague-Dawley | 2009 |
Escalated regeneration in sciatic nerve crush injury by the combined therapy of human amniotic fluid mesenchymal stem cells and fermented soybean extracts, Natto.
Attenuation of inflammatory cell deposits and associated cytokines prevented the apoptosis of transplanted stem cells in a sciatic nerve crush injury model. Suppression of inflammatory cytokines by fermented soybean extracts (Natto) was also beneficial to nerve regeneration. In this study, the effect of Natto on transplanted human amniotic fluid mesenchymal stem cells (AFS) was evaluated. Peripheral nerve injury was induced in SD rats by crushing a sciatic nerve using a vessel clamp. Animals were categorized into four groups: Group I: no treatment; Group II: fed with Natto (16 mg/day for 7 consecutive days); Group III: AFS embedded in fibrin glue; Group IV: Combination of group II and III therapy. Transplanted AFS and Schwann cell apoptosis, inflammatory cell deposits and associated cytokines, motor function, and nerve regeneration were evaluated 7 or 28 days after injury. The deterioration of neurological function was attenuated by AFS, Natto, or the combined therapy. The combined therapy caused the most significantly beneficial effects. Administration of Natto suppressed the inflammatory responses and correlated with decreased AFS and Schwann cell apoptosis. The decreased AFS apoptosis was in line with neurological improvement such as expression of early regeneration marker of neurofilament and late markers of S-100 and decreased vacuole formation. Administration of either AFS, or Natto, or combined therapy augmented the nerve regeneration. In conclusion, administration of Natto may rescue the AFS and Schwann cells from apoptosis by suppressing the macrophage deposits, associated inflammatory cytokines, and fibrin deposits. Topics: Amniotic Fluid; Animals; Apoptosis; Cytokines; Fibrin; Fibrin Tissue Adhesive; Inflammation; Macrophages; Mesenchymal Stem Cell Transplantation; Nerve Crush; Nerve Regeneration; Nerve Tissue Proteins; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Recovery of Function; Schwann Cells; Sciatic Nerve; Soy Foods | 2009 |
Comparing DIC scores: not an easy task indeed.
Topics: Blood Coagulation; Blood Platelets; Cardiology; Clinical Trials as Topic; Disseminated Intravascular Coagulation; Fibrin; Humans; Inflammation; Kinetics; Platelet Count; Prognosis; Prothrombin Time; Risk | 2009 |
Immunohistochemical characterization of neotissues and tissue reactions to septal defect-occlusion devices.
We sought to evaluate tissue reactions within and at the surface of devices for interventional therapy of septal defects and to identify antigen characteristics of neotissues.. Atrial or ventricular septal defect-occlusion devices (Amplatzer, n=7; Cardioseal/Starflex, n=3) were processed using a uniform protocol after surgical removal from humans (implantation time, 5 days to 4 years). Devices were fixed in formalin and embedded in methylmethacrylate. Serial sections were obtained by sectioning with a diamond cutter and grinding, thus saving the metal/tissue interface for histologic evaluation. Immunohistochemical staining was performed using conventional protocols. Superficial endothelial cells stained positive for von Willebrand factor. Within the newly formed tissues, fibroblast-like cells were identified with a time-dependent expression of smooth muscle cell maturation markers (smooth muscle actin, smooth muscle myosin, h-caldesmon, and desmin) beside extracellular matrix components. Neovascularization of the newly formed tissues was demonstrated with the typical immunohistochemical pattern of capillaries and small vessels. Inflammatory cells could be identified as macrophages (CD68+) and both T-type and B-type lymphocytes (CD3+, CD79+).. This is the first presentation of results from serial immunohistochemical staining of a collection of explanted human septal-occlusion devices. A time-dependent maturation pattern of the fibroblast-like cells in the neotissues around the implants could be described. Neoendothelialization was seen in all specimens with implantation times of 10 weeks or more. The time course of neoendothelialization, as seen in our study, further supports the clinical practice of anticoagulant or antiplatelet therapy for 6 months after implantation. This time interval should be sufficient to prevent thromboembolic events due to thrombus formation at the foreign surface of cardiovascular implants. Topics: Biomarkers; Cardiac Catheterization; Cell Proliferation; Coronary Vessels; Device Removal; Endothelial Cells; Fibrin; Fibroblasts; Foreign-Body Reaction; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Immunohistochemistry; Inflammation; Prosthesis Design; Prosthesis Failure; Septal Occluder Device; Time Factors; Tunica Intima | 2009 |
Fibrin scaffold promotes adenoviral gene transfer and controlled vector delivery.
Gene therapy using adenoviral vectors in tissue regeneration is hindered by a short duration of transgene expression. It is hypothesized that a fibrin scaffold will enhance delivery of the adenovirus to a wound site, precluding the need for high repeated doses. It was aimed to analyze whether fibrin could deliver a low single dose of viral vector to a wound site, without compromising transfection efficiency. Fibrin scaffold containing adenovirus encoding beta-galactosidase, fibrin alone, adenovirus alone, and no treatment groups were applied to a rabbit ear ulcer model. beta-Galactosidase transgene expression was measured at 7 and 14 days. Transgene expression was enhanced in the fibrin containing adenovirus group at 7 days. By 14 days, there was low expression and no difference between groups. Stereological methods assessing wound healing aimed to determine whether the adenovirus capsid elicited an unfavorable inflammatory response and whether fibrin's beneficial properties were altered by addition of adenovirus. The fibrin adenovirus group showed a wound-healing response similar to fibrin alone, showing maximum cellularity and angiogenesis at 7 days. By 14 days, cellularity and angiogenesis subsided, and this effect was not inhibited by the presence of adenovirus. Adenovirus alone did not cause an unfavorable inflammatory response. It is concluded the fibrin aids in the delivery of a low-dose viral vector, thereby avoiding a chronic inflammatory response, and allowing superior transfection than viral vector alone. This has wide-ranging implications on the use of viral vectors in tissue engineering. Topics: Adenoviridae; Animals; beta-Galactosidase; Blood Vessels; Cell Nucleus; Diffusion; Drug Delivery Systems; Fibrin; Fibroblasts; Gene Transfer Techniques; Genetic Vectors; Immunohistochemistry; Inflammation; Neovascularization, Physiologic; Rabbits; Surface Properties; Tissue Scaffolds; Transgenes | 2009 |
Citrullinated fibrinogen inhibits thrombin-catalysed fibrin polymerization.
Citrullination is the post-translational modification of arginine residues by peptidylarginine deiminases (PADIs). Fibrinogen is one substrate of PADIs under physiological conditions. Fibrinogen is an important factor for blood coagulation and inducing inflammation. The citrullinated form of fibrinogen appears in rheumatoid arthritis synovial tissue together with the production of autoantibodies that target self-peptides containing citrulline. However, whether the function of fibrinogen changes after citrullination remains unclear. We found that citrullinated fibrinogen markedly impairs the function of thrombin-catalysed fibrin polymerization and also inhibits fibrin formation. Increased citrullinated fibrinogen might thus affect the balance between coagulation and fibrinolysis and alter antigenicity under physiological conditions. These data suggest that citrullination of proteins could physiologically change functions and subsequently generate pro-inflammatory conditions and autoimmune reactions. Topics: Arginine; Blood Coagulation; Catalysis; Citrulline; Edetic Acid; Fibrin; Fibrinogen; Humans; Inflammation; Kinetics; Peptides; Substrate Specificity; Thrombin; Time Factors | 2008 |
Proinflammatory cytokines, fibrinolytic system enzymes, and biochemical indices in children with infectious para-pneumonic effusions.
In children, pleural empyema is a recognized complication of severe pneumonia and is characterized by loculated effusions with fibrin septations. The aim of this study was to evaluate the relationship between proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6], intrapleural fibrinolytic system enzymes [tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1)], and common biochemical indices during pleural infection.. Children with pneumonia complicated by para-pneumonic effusions were enrolled into our study and underwent real-time chest sonography. The patients were divided into 3 groups by ultrasound using a recognized staging system of pleural effusions. Staging of progressive pleural infection was used to correlate with the characteristics of pleural effusions. The correlation of various pleural variables with the formation of complicated para-pneumonic effusions (CPE) was performed and pleural variables for predicting subsequent intervention procedures were also analyzed.. A total of 57 patients were enrolled in the present study. Univariate analysis revealed that the amounts of biochemical indices (pH, glucose, lactate dehydrogenase), proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), and fibrinolytic system enzymes (tPA, PAI-1) were significantly different with the progressive stages of para-pneumonic effusions (Ptrend < 0.05). For all proinflammatory cytokines, a positive correlation was found with lactate dehydrogenase and PAI-1, whereas a negative correlation was found with pH, glucose, and tPA. Moreover, these cytokines were also significantly correlated with PAI-1 in both non-CPE and CPE. The pleural fluid findings of IL-1beta (> or =50 pg/mL), PAI-1 (> or =1252 ng/mL), and pH (< or =7.30) were the most significant predictive factors for subsequent intervention procedures (P < 0.001).. The increased release of proinflammatory cytokines in pleural fluid caused by bacteria may result in an imbalance of the fibrinolytic system, which can subsequently lead to fibrin deposition and intervention procedures. Topics: Adolescent; Child; Child, Preschool; Cytokines; Female; Fibrin; Glucose; Humans; Hydrogen-Ion Concentration; Infant; Inflammation; L-Lactate Dehydrogenase; Male; Plasminogen Activator Inhibitor 1; Pleural Effusion; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Tissue Plasminogen Activator; Ultrasonography | 2008 |
Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study.
The long-term safety of drug-eluting stents (DES) for acute myocardial infarction (AMI) remains uncertain. Using autopsy data, we evaluated the pathological responses of the stented segment in patients treated with DES for AMI and compared with patients with stable angina.. From the CVPath Registry of 138 DES autopsies, we identified 25 patients who presented with AMI and had an underlying necrotic core with a ruptured fibrous cap. Twenty-six patients who had stable angina with thick-cap fibroatheroma treated by DES were selected as controls. Histomorphometric analysis was performed in patients with >30-day stent duration. We compared the response to stenting at the culprit site in these 2 groups and to nonculprit sites within each stent. Late stent thrombosis was significantly less frequent in stable (11%) than in AMI (41%; P=0.04) patients. Although neointimal thickness in the AMI culprit site was significantly less (median, 0.04 mm; interquartile range [IQR], 0.02 to 0.09 mm), the prevalence of uncovered struts (49%; IQR, 16% to 96%), fibrin deposition (63+/-28%), and inflammation (35%; IQR, 27% to 49%) were significantly greater compared with the culprit site in stable patients (neointimal thickness: 0.11 mm [IQR, 0.07 to 0.21 mm], P=0.008; uncovered struts: 9% [IQR, 0% to 39%], P=0.01; fibrin: 36+/-27%, P=0.008; inflammation, 17% [IQR, 7% to 25%], P=0.003) and the nonculprit site within each stent.. Vessel healing at the culprit site in AMI patients treated with DES is substantially delayed compared with the culprit site in patients receiving DES for stable angina, emphasizing the importance of underlying plaque morphology in the arterial response to DES. Our data suggest an increased risk of thrombotic complications in patients treated with DES for AMI. Topics: Adult; Aged; Angina Pectoris; Autopsy; Coronary Vessels; Drug-Eluting Stents; Female; Fibrin; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Prosthesis Implantation; Retrospective Studies; Thrombosis; Time Factors; Treatment Outcome | 2008 |
Relations of biomarkers representing distinct biological pathways to left ventricular geometry.
Several biological pathways are activated concomitantly during left ventricular (LV) remodeling. However, the relative contribution of circulating biomarkers representing these distinct pathways to LV geometry is unclear.. We evaluated 2119 Framingham Offspring Study participants (mean age, 57 years; 57% women) who underwent measurements of biomarkers of inflammation (C-reactive protein), hemostasis (fibrinogen and plasminogen activator inhibitor-1), neurohormonal activation (B-type natriuretic peptide), and renin-angiotensin-aldosterone system (aldosterone and renin modeled as a ratio [ARR]) and echocardiography at a routine examination. LV geometry was defined on the basis of sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT): normal (LVM and RWT <80th percentile), concentric remodeling (LVM <80th percentile but RWT >or=80th percentile), eccentric hypertrophy (LVM >or=80th percentile but RWT <80th percentile), and concentric hypertrophy (LVM and RWT >or=80th percentile). We related the biomarker panel to LV geometry using polytomous logistic regression adjusting for clinical covariates and used backwards elimination to identify a parsimonious set of biomarkers associated with LV geometry. Modeled individually, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1, and ARR were related to LV geometry (P<0.01). In multivariable analyses, the biomarker panel was significantly related to altered LV geometry (P<0.0001). On backwards elimination, logARR alone was significantly and positively associated with eccentric (odds ratio per SD increment, 1.20; 95% confidence interval, 1.05 to 1.37) and concentric LV hypertrophy (odds ratio per SD increment, 1.29; 95% confidence interval, 1.06 to 1.58).. Our cross-sectional observations on a large community-based sample identified ARR as a key correlate of concentric and eccentric LV hypertrophy, consistent with a major role for the renin-angiotensin-aldosterone system in LV remodeling. Topics: Aldosterone; Biomarkers; C-Reactive Protein; Cardiomegaly; Electrocardiography; Female; Fibrin; Heart Ventricles; Humans; Inflammation; Male; Middle Aged; Natriuretic Peptide, Brain; Plasminogen Activator Inhibitor 1; Regression Analysis; Renin-Angiotensin System; Ultrasonography; Ventricular Function, Left; Ventricular Remodeling | 2008 |
Adverse effects associated with the use of porcine cross-linked collagen implants in an experimental model of incisional hernia repair.
Porcine cross-linked collagen (PermaCol, PCL; TSL, Aldershot, United Kingdom) has been proposed as permanent biomaterial in incisional hernia repair. We evaluated the biocompatibility of PCL in an established animal model.. In 10 Sprague Dawley rats, two hernias per animal were created in the abdominal wall left and right of the linea alba (1.5 cm in diameter), and the peritoneum was spared. The lesions were left untreated for 10 days, until incisional hernias developed. These defects were covered with non-perforated (out-of-the-box, n = 12) or perforated (modified; n = 8) PCL (2 x 2 cm). In a first step, 12 non-perforated implants were tested in a short-term observation period of 17 days. Eight of these non-perforated implants were fibrin sealed (0.3 mL, Tissucol; Baxter, Vienna, Austria), whereas four non-perforated implants were sutured with non-resorbable material. In a second step, perforations were added as modification to PCL to facilitate drainage of fluids, cell ingrowth, and transgression of fibrin sealant. All perforated implants were fibrin sealed and included in a long-term observation period of 3 months. The observation periods allowed the evaluation of the complete degradation of the fibrin sealant fixation after 2 weeks and of the implant integration in a chronic timeframe. Implant sites were analyzed macroscopically and histologically.. All PCL samples elicited strong local inflammation with signs of foreign body reaction. Integration of perforated PCL appeared limited after 3 months. Three animals had to be euthanized prior to intended time points because of transcutaneous migration of implants.. In an experimental model of incisional hernia repair, PCL does not integrate well in the abdominal wall and shows poor biocompatibility. Topics: Animals; Biocompatible Materials; Collagen; Digestive System Surgical Procedures; Fibrin; Foreign-Body Migration; Herniorrhaphy; Implants, Experimental; Inflammation; Male; Models, Animal; Rats; Rats, Sprague-Dawley; Surgical Mesh; Swine | 2008 |
Short-term effects of biocorrodible iron stents in porcine coronary arteries.
Biocorrodible iron stents carry the potential to overcome limitations, such as chronic inflammation and premature recoil, posed by biodegradable polymer and magnesium alloy stents. This study aimed to test the safety and efficacy of biocorrodible iron stents in porcine coronary arteries.. Iron stents and cobalt chromium stents were randomly deployed in the coronary arteries of juvenile domestic pigs. Animals were sacrificed at 28 days, and the vessels were fixed and processed for histochemistry.. At 28 days, iron stents started to show signs of degradation without evidence of stent particle embolization or thrombosis without traces of excess inflammation, or fibrin deposition. At 28 days, the surface of the iron stent struts was black to brown and the vascular wall adjacent to the iron stent had a brownish tinge. There were no statistically significant differences in any of the measured parameters between segments implanted with iron and cobalt chromium stents. There were also no adverse effects in the persistent areas.. The current study demonstrates that stents made of biocorrodible iron are safe. In some of the measured parameters, such as intimal thickness, intimal area, and percentage occlusion, there was a trend in favor of the iron stents. Topics: Animals; Biocompatible Materials; Chromium; Cobalt; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Coronary Vessels; Fibrin; Inflammation; Iron Compounds; Stents; Swine | 2008 |
Hemolysis-associated hypercoagulability in sickle cell disease: the plot (and blood) thickens!
Topics: Anemia, Sickle Cell; Endothelial Cells; Fibrin; Flow Cytometry; Hemolysis; Hemostasis; Humans; Hypertension, Pulmonary; Inflammation; Models, Biological; Monocytes; Thrombophilia | 2008 |
Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation.
Tissue factor (TF) activation of the coagulation proteases enhances inflammation in animal models of arthritis and endotoxemia, but the mechanism of this effect is not yet fully understood - in particular, whether this is primarily due to fibrin formation or through activation of protease activated receptors (PARs).. We induced extravascular inflammation by injection of recombinant soluble murine TF (sTF1-219) in the hind paw. The effects of thrombin inhibition, fibrinogen and platelet depletion were evaluated, as well as the effects of PAR deficiency using knockout mice deficient for each of the PARs.. Injection of soluble TF provoked a rapid onset of paw swelling. Inflammation was confirmed histologically and by increased serum IL-6 levels. Inflammation was significantly reduced by depletion of fibrinogen (P < 0.05) or platelets (P = 0.015), and by treatment with hirudin (P = 0.04) or an inhibitor of activated factor VII (P < 0.001) compared with controls. PAR-4-deficient mice exhibited significantly reduced paw swelling (P = 0.003). In contrast, a deficiency in either PAR-1, PAR-2 or PAR-3 did not affect the inflammatory response to soluble TF injection.. Our results show that soluble TF induces acute inflammation through a thrombin-dependent pathway and both fibrin deposition and platelet activation are essential steps in this process. The activation of PAR-4 on platelets is crucial and the other PARs do not play a major role in soluble TF-induced inflammation. Topics: Animals; Blood Coagulation; Blotting, Western; Factor VIIa; Fibrin; Immunohistochemistry; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Activation; Receptors, Proteinase-Activated; Thromboplastin | 2008 |
The use of therapeutic gene eNOS delivered via a fibrin scaffold enhances wound healing in a compromised wound model.
Diabetic healing is marked by a reduced nitric oxide (NO) production at the wound site. This study aimed to investigate whether a fibrin scaffold would enhance the delivery of adenovirus encoding endothelial nitric oxide synthase (eNOS), one of the enzymes responsible for NO production, resulting in more NO production, and enhanced healing. An alloxan rabbit ear ulcer model was used to investigate healing, in response to the following treatments: fibrin containing AdeNOS, AdeNOS alone, fibrin alone and no treatment. Immunohistochemistry to detect eNOS expression and histological evaluation of healing were assessed at 7 and 14 days. eNOS expression was significantly greater in the fibrin containing AdeNOS group at 14 days compared to all other groups. Furthermore, this group showed a significantly faster rate of epithelialisation than all other groups. The volume of inflammatory cells was highest in the fibrin containing AdeNOS group at 7 days, which dropped significantly by 14 days. Likewise, the surface area and length of vessels reduced significantly in the fibrin containing AdeNOS group between 7 and 14 days indicating tissue remodelling, but remained stable in all other groups. Regression analysis showed that the epithelialisation rate was significantly affected by change in eNOS expression, inflammation, and surface area and length of vessels over time in the fibrin containing AdeNOS group. It was concluded that fibrin delivery of AdeNOS resulted in enhanced eNOS expression, inflammatory response, and a faster rate of re-epithelialisation. Topics: Adenoviridae; Animals; Blood Vessels; Collagen; Ear; Fibrin; Genetic Therapy; Immunohistochemistry; Inflammation; Nitric Oxide; Nitric Oxide Synthase Type III; Rabbits; Time Factors; Tissue Scaffolds; Transfection; Ulcer; Wound Healing | 2008 |
High-mobility group box 1 protein promotes development of microvascular thrombosis in rats.
Sepsis is a life-threatening disorder resulting from systemic inflammatory and coagulatory responses to infection. High-mobility group box 1 protein (HMGB1), an abundant intranuclear protein, was recently identified as a potent lethal mediator of sepsis. However, the precise mechanisms by which HMGB1 exerts its lethal effects in sepsis have yet to be confirmed. We recently reported that plasma HMGB1 levels correlated with disseminated intravascular coagulation (DIC) score, indicating that HMGB1 might play an important role in the pathogenesis of DIC.. To investigate the mechanisms responsible for the lethal effects of HMGB1, and more specifically, to explore the effects of HMGB1 on the coagulation system.. Rats were exposed to thrombin with or without HMGB1, and a survival analysis, pathologic analyses and blood tests were conducted. The effects of HMGB1 on the coagulation cascade, anticoagulant pathways and surface expression of procoagulant or anticoagulant molecules were examined in vitro.. Compared to thrombin alone, combined administration of thrombin and HMGB1 resulted in excessive fibrin deposition in glomeruli, prolonged plasma clotting times, and increased mortality. In vitro, HMGB1 did not affect clotting times, but inhibited the anticoagulant protein C pathway mediated by the thrombin-thrombomodulin complex, and stimulated tissue factor expression on monocytes.. These findings demonstrate the procoagulant role of HMGB1 in vivo and in vitro. During sepsis, massive accumulation of HMGB1 in the systemic circulation would promote the development of DIC. Topics: Animals; Blood Coagulation; Blood Coagulation Tests; Cells, Cultured; Coagulants; Cytokines; Disease Models, Animal; Disseminated Intravascular Coagulation; Enzyme Activation; Fibrin; Hemolysis; High Mobility Group Proteins; HMGB1 Protein; Humans; Inflammation; Kidney; Lung; Male; Monocytes; Protein C; Rats; Rats, Sprague-Dawley; Repressor Proteins; Thrombin; Thromboplastin; Thrombosis | 2007 |
Fibrin D-dimer fragments enhance inflammatory responses in macrophages: role in advancing atherosclerosis.
1. Fibrin D-dimer is considered a consistent and independent marker of the risk of cardiovascular disease in population studies, as well as being related to atherosclerosis severity in patients. However, the role of fibrin D-dimer in macrophage-derived foam cell formation during atherogenesis remains unclear. 2. In the present study, using microarray techniques, we determined the effects of 100 ng/mL fibrin D-dimer fragments on macrophage cell function in atherosclerosis by investigating the expression levels of 128 genes related to the atherosclerotic pathophysiological processes. 3. The results showed that 27 genes were enhanced by D-dimer fragments to over twofold of control. These 27 genes belonged to six groups and included adhesion molecules, extracellular molecules, molecules related to lipid transport and metabolism, cell growth and proliferation molecules, transcription regulators and genes responsive to stress. We proceeded to determine the expression levels of five of these genes (intercellular adhesion molecule-1, matrix metalloproteinase-9, oxidized low-density lipoprotein receptor 1, vascular endothelial growth factor A and peroxisome proliferator-activated receptor alpha) using SYBR real-time polymerase chain reaction. The results confirmed gene upregulation, similar to the results obtained with the microarray, following treatment with D-dimer. 4. Therefore, the present study provides direct evidence regarding the pro-atherosclerotic role of D-dimer in macrophage function, which is mainly to enhance the inflammatory response during macrophage-derived foam cell formation. Topics: Atherosclerosis; Cell Adhesion Molecules; Cell Proliferation; Fibrin; Gene Expression Regulation; Gene Library; Humans; Indicators and Reagents; Inflammation; Lipid Metabolism; Macrophages; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Reverse Transcriptase Polymerase Chain Reaction; RNA; U937 Cells; Up-Regulation | 2007 |
Coagulation abnormalities associated with severe isolated traumatic brain injury: cerebral arterio-venous differences in coagulation and inflammatory markers.
Although coagulopathy is known to be the major contributor to a poor outcome of traumatic brain injury (TBI), the mechanisms that trigger coagulation abnormalities have not been studied in detail. We undertook a prospective observational study at a neurosurgical ICU (NICU) in a university hospital. We examined 11 patients with severe isolated TBI, at admittance to the hospital and during the next 3 days. We collected cerebrovenous blood samples from a jugular bulb catheter, arterial blood, and cerebrospinal fluid (CSF) samples. We measured concentrations of thrombin-antithrombin complex (TAT), fibrin D-dimer (DD), prothrombin fragment 1 + 2 (F1 + 2), interleukin-6 (IL-6), and complement complex (C5b-9). All patients had some degree of consumption coagulopathy at the study start and a tendency to thrombocytopenia during the next few days. Levels of DD (3.6 +/- 2.7 mg/L), TAT (86 +/- 72 microg/L) and F1 + 2 (5.9 +/- 6.8 nmol/L) were significantly increased shortly after the trauma compared to reference values, with considerable transcranial gradients for TAT (49 microg/L) and F1 + 2 (3.2 nmol/L). Compared to controls, IL-6 levels were increased more than a hundredfold in both blood (283 +/- 192 ng/L) and CSF (424 +/- 355 ng/L) samples, with a transcranial gradient at the study start (107 ng/L). C5b-9 levels were moderately increased in blood samples, 270 +/- 114 microg/L, versus controls, 184 +/- 39 (p < 0.05). We conclude that activation of the coagulation system takes place during the passage of blood through the damaged brain, and is already evident hours after the trauma. IL-6 and activation of the complement system (C5b-9) co-vary with hemostatic parameters in TBI patients. Topics: Accidents; Adult; Antithrombins; Biomarkers; Blood Coagulation Disorders; Blood Coagulation Tests; Brain Injuries; Complement Membrane Attack Complex; Female; Fibrin; Glasgow Coma Scale; Humans; Inflammation; Interleukin-6; International Normalized Ratio; Male; Middle Aged; Peptide Fragments; Prospective Studies; Prothrombin; Thrombin | 2007 |
Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in experimental glomerulonephritis in mice.
The role of thrombospondin 2 (TSP2) was investigated in an anti-glomerular basement membrane (GBM) nephritis model that compared TSP2-null mice with wild-type (WT) controls. TSP2-null mice were analyzed for kidney function, renal cortical matrix expansion, influx of inflammatory cells, proliferation, and apoptosis, as well as for capillary rarefaction after induction of anti-GBM disease. Whereas the renal cortex of normal control WT mice did not show any detectable TSP2 staining above background, TSP2 protein expression was clearly upregulated in anti-GBM disease. TSP2 deficiency led to an accelerated and enhanced inflammatory response, as indicated by the influx of CD4(+) and CD8a(+) cells and monocytes/macrophages. Glomerular fibrin deposition and a matrix-remodeling response were also observed, as indicated by collagens I and IV staining and a proliferative response within the renal interstitium. These changes were accompanied by increased matrix metalloproteinase 2 activity and enhanced alpha-smooth muscle actin staining in the TSP2-null mice. Neither a compensatory increase in TSP1 nor increased phosphorylation of Smad 2/3, an indicator for TGF-beta activity, was observed. The proliferative response of the peritubular endothelium was accelerated and enhanced, leading to a reversal of capillary rarefaction in TSP2-null mice, whereas interstitial cell death was equivalent to that in WT mice. In conclusion, the lack of the matricellular protein TSP2 in mice accelerates and enhances several responses to renal injury and reveals an important role for TSP2 as a major endogenous antiangiogenic and matrix metalloproteinase 2-regulating factor in renal disease. Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cell Adhesion Molecules; Cell Proliferation; Fibrin; Glomerular Basement Membrane; Glomerulonephritis; Inflammation; Kidney Cortex; Kidney Glomerulus; Matrix Metalloproteinase 2; Mice; Mice, Knockout; Neovascularization, Pathologic; Thrombospondins | 2007 |
Thrombus formation without platelets under inflammatory condition: an in vitro study.
Platelet derived microvesicles, which are shed from platelets upon platelet activation, interact with monocytes in the blood. In this study the nature of this interaction was characterized in a model system with the monocytic cell line MM6 and isolated platelet derived microvesicles (PMV). The interaction of PMV with MM6 is separated in two consecutive steps, which are partially overlapped in time. In a first step there is an immediate conjugate formation with single MM6 and PMV, which was proved microscopically and by cytometry measurements. This process is dependent on CD62P, determined by an inhibition after pre-incubation with anti-CD62P. After a lag time of 4 min this process is supplemented by an aggregate formation of single conjugates, which leads finally to one macroscopic visible aggregate. The Nature of this aggregate was characterized by immunohistochemistry and laser aggregatometry. An addition of GPRP blocks the formation of a fibrin network and also the aggregate formation, proving the necessity of fibrin network formation. This was also shown by diminishing the aggregate formation by addition of hirudin. Finally fluorescent microscopic images proved the necessity of a fibrin network holding MM6 cell/PMV aggregates together. Even pure PMV can form such an aggregate only visible as thin film and less stable as the cell PMV aggregate. The described process might be important in vivo causing thrombotic events without direct involvement of platelets. Especially in situations with extreme PMV levels, such as acute coronary heart disease, trauma and sepsis, these events could lead to the appearance of haemostatic complications. Topics: Blood Coagulation; Blood Platelets; Cell Line; Cell Membrane; Fibrin; Humans; In Vitro Techniques; Inflammation; Microscopy, Confocal; Monocytes; Thrombosis | 2007 |
Effects of intra-abdominal administration of recombinant tissue plasminogen activator on coagulation, fibrinolysis and inflammatory responses in experimental polymicrobial peritonitis.
Peritonitis represents a procoagulant state because of activated coagulation and inhibited fibrinolysis. Intra-abdominal fibrin deposition-entrapping bacteria-prevents bacterial spread but impairs bacterial clearance. Activating intra-abdominal fibrinolysis by recombinant tissue-type plasminogen activator (r-tPA) early during peritonitis may enhance bacterial clearance and reduce inflammation. This study examines effects of abdominal r-tPA lavage on local and distant coagulation, fibrinolysis, and inflammatory responses in experimental polymicrobial peritonitis. Twenty-four hours after cecal ligation and puncture, mice were exposed to therapeutic abdominal lavage with varying doses of r-tPA or saline (controls). Coagulation, fibrinolysis, and inflammation were assessed in abdominal, systemic, and pulmonary compartments (n = 6 per group per time point). Survival was assessed during 96 h (n = 16 per group). Highest-dose (2 mg/mL) r-tPA lavage caused immediate death. High-dose (0.5 mg/mL) r-tPA lavage increased fibrinolysis, demonstrated by low abdominal plasminogen activator inhibitor 1 levels and elevated pulmonary tPA levels, resulting in reduced abdominal bacterial load, chemokine levels, leukocyte influx, and thrombin generation, along with less pulmonary fibrin depositions and organ damage on histological examination (P < 0.05 vs. saline lavage). Low-dose (0.05 mg/mL) r-tPA lavage showed hardly any effect compared with saline lavage. Adversely, abdominal and plasma interleukin (IL) 12 were elevated, whereas IL-10 levels were decreased after high-dose r-tPA lavage (P < 0.05 vs. saline). Survival rate was not affected by any dose of r-tPA lavage compared with saline lavage. Delayed local stimulation of fibrinolysis by peritoneal r-tPA lavage enhanced intra-abdominal bacterial clearance and reduced intra- and extra-abdominal coagulation responses in a dose-dependent manner. Survival rate was unaffected likely due to adverse changes in IL-12 and IL-10 levels. Topics: Animals; Blood Coagulation; Cecum; Chemokines; Dose-Response Relationship, Drug; Fibrin; Fibrinolysis; Immunohistochemistry; Inflammation; Interleukin-10; Interleukin-12; Male; Mice; Mice, Inbred C57BL; Peritoneal Lavage; Peritonitis; Plasminogen Activator Inhibitor 1; Recombinant Proteins; Sodium Chloride; Survival Rate; Thrombin; Tissue Plasminogen Activator | 2007 |
Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease.
Cerebrovascular dysfunction contributes to the pathology and progression of Alzheimer's disease (AD), but the mechanisms are not completely understood. Using transgenic mouse models of AD (TgCRND8, PDAPP, and Tg2576), we evaluated blood-brain barrier damage and the role of fibrin and fibrinolysis in the progression of amyloid-beta pathology. These mouse models showed age-dependent fibrin deposition coincident with areas of blood-brain barrier permeability as demonstrated by Evans blue extravasation. Three lines of evidence suggest that fibrin contributes to the pathology. First, AD mice with only one functional plasminogen gene, and therefore with reduced fibrinolysis, have increased neurovascular damage relative to AD mice. Conversely, AD mice with only one functional fibrinogen gene have decreased blood-brain barrier damage. Second, treatment of AD mice with the plasmin inhibitor tranexamic acid aggravated pathology, whereas removal of fibrinogen from the circulation of AD mice with ancrod treatment attenuated measures of neuroinflammation and vascular pathology. Third, pretreatment with ancrod reduced the increased pathology from plasmin inhibition. These results suggest that fibrin is a mediator of inflammation and may impede the reparative process for neurovascular damage in AD. Fibrin and the mechanisms involved in its accumulation and clearance may present novel therapeutic targets in slowing the progression of AD. Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Disease Models, Animal; Disease Progression; Fibrin; Fibrinogen; Inflammation; Mice; Mice, Transgenic; Models, Biological; Permeability; Plasminogen; Tranexamic Acid | 2007 |
Fibrin clot structure in patients with end-stage renal disease.
Fibrin clots with reduced permeability, increased clot stiffness and reduced fibrinolysis susceptibility may predispose to cardiovascular disease (CVD). Little is known, however, about the structure of fibrin clots in patients with end-stage renal disease (ESRD). These patients suffer from a high risk of CVD in addition to their chronic low-grade inflammation. Using permeability, compaction and turbidity studies in 22 ESRD patients and 24 healthy controls, fibrin clots made from patient plasma were found to be less permeable (p < 0.001), less compactable (p < 0.001), and less susceptible to fibrinolysis (p < 0.001) than clots from controls. The maximum rate of turbidity increase was also higher for the patients than controls (p < 0.001), and scanning electron microscopy revealed higher clot density of fibrin fibers in clots from patients than clots from controls (p < 0.001). Patients had higher plasma concentrations of fibrinogen, C-reactive protein and interleukin 6 than controls. These plasma markers of inflammation correlated significantly with most of the fibrin structure characteristics observed in the patients. In contrast, plasma markers of azothemia showed no such correlations. The results suggest that in ESRD patients fibrin clots are significantly different from healthy controls, and that the fibrin structure characteristics in the patients are associated primarily with the inflammatory plasma milieu rather than with level of azothemia. Topics: Azotemia; Biomarkers; Blood Coagulation; Case-Control Studies; Female; Fibrin; Fibrinolysis; Humans; Inflammation; Kidney Failure, Chronic; Male; Microscopy, Electron, Scanning; Middle Aged; Nephelometry and Turbidimetry; Permeability | 2007 |
Chronic plasminogen activator inhibitor-1 (PAI-1) overexpression dampens CD25+ lymphocyte recruitment after lipopolysaccharide endotoxemia in mouse lung.
Plasma plasminogen activator inhibitor-1 (PAI-1) level rises during sepsis and confers a worse prognosis. PAI-1 participation to sepsis has been poorly documented and was mainly associated with fibrin deposits. Beside fibrin deposits, increased tissue PAI-1 expression may contribute to the poor outcome of endotoxemia through other mechanisms.. During lipopolysaccharide (LPS) challenge, the role of PAI-1 in the early phase of inflammation was examined in the lungs of transgenic mice that either overexpress or lack the PAI-1 gene (PAI-1Tg or PAI-1(-/-)).. Analysis of leukocytes revealed that neutrophil and macrophage infiltrations did not differ for PAI-1Tg and wild-type (WT) mice. Remarkably, CD25+ lymphocyte infiltration was totally blunted in PAI-1Tg lungs and inversely correlated with fibrin depositions. In parallel, mRNA levels of the regulatory T cell (Treg) markers FoxP3, CTLA-4, and GITR were significantly lower in PAI-1Tg than in WT lungs after LPS challenge. These data are supported by opposite results in PAI-1(-/-) lungs. The systemic compartments (spleen and peripheral blood) showed no decrease in CD25+, CD4+ CD25+ lymphocytes, and Treg markers in PAI-1Tg mice after LPS injection compared with WT mice. In addition, plasma and lung concentrations of interleukin-6 (IL-6) and macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly higher in PAI-1Tg mice than WT mice.. Our results suggest that chronic tissue PAI-1 overexpression influences the early phase of the inflammatory response during endotoxemia through the control of T lymphocyte traffic. Topics: Animals; Antigens, CD; Antigens, Differentiation; Chemokine CCL3; Chemotaxis, Leukocyte; CTLA-4 Antigen; Disease Models, Animal; Endotoxemia; Fibrin; Forkhead Transcription Factors; Glucocorticoid-Induced TNFR-Related Protein; Immunity, Innate; Inflammation; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Interleukin-6; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Knockout; Mice, Transgenic; Neutrophils; Pulmonary Fibrosis; Receptors, Nerve Growth Factor; Receptors, Tumor Necrosis Factor; RNA, Messenger; Serpin E2; Serpins; T-Lymphocytes; T-Lymphocytes, Regulatory; Time Factors; Up-Regulation | 2007 |
Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif.
Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib-) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin alphaMbeta2 binding motif (Fibgamma390-396A) or the alphaIIbbeta3 platelet integrin-binding motif (FibgammaDelta5), were challenged with collagen-induced arthritis (CIA). Fib- mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibgamma390-396A mice, which retain full clotting function. In contrast, arthritis in FibgammaDelta5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib- and Fibgamma390-396A mice with CIA displayed reduced local expression of TNF-alpha, IL-1beta, and IL-6, which suggests that alphaMbeta2-mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-alpha expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to alphaMbeta2-mediated inflammatory processes. Topics: Amino Acid Motifs; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cartilage, Articular; Cattle; Collagen Type II; Cytokines; Fibrin; Fibrinogen; Gene Targeting; Humans; Inflammation; Joints; Leukocytes; Macrophage-1 Antigen; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mutation | 2007 |
Haemophilus somnus activation of brain endothelial cells: potential role for local cytokine production and thrombosis in central nervous system (CNS) infection.
Thrombotic meningoencephalitis (TME) is a neurological condition in cattle characterized by fibrinopurulent meningitis with hemorrhage, abscess formation and thrombotic vasculitis throughout the central nervous system. The etiologic agent of TME is Haemophilus somnus, a gram-negative pleomorphic coccobacillus. Although the pathogenesis of TME is not well understood, the propensity of H. somnus to cause vasculitis and intravascular thrombosis suggests a critical role for the interactions between the bacteria and endothelial cells in inciting the disease. The goal of this study was to determine if H. somnus elicits an inflammatory and procoagulative response in bovine brain microvascular endothelial cells (BBEC) in vitro. We demonstrate that BBEC exposed to H. somnus secrete significant levels of the proinflammatory and procoagulative cytokines TNF-alpha and IL-1beta. BBEC treated with H. somnus also display increased levels of IL-6 mRNA, another cytokine associated with coagulopathy in vivo. H. somnus-treated BBEC exhibited increased procoagulant activity and tissue factor expression and activity, along with a decreased ability to activate protein C and decreased expression of thrombomodulin mRNA. These changes would be expected to promote thrombus formation in vessels of the CNS, and potentially contribute to the pathogenesis of TME. Topics: Animals; Brain; Cattle; Central Nervous System Infections; Coagulants; Cytokines; Endothelial Cells; Fibrin; Haemophilus somnus; Inflammation; Models, Biological; Protein C; Thromboplastin; Thrombosis | 2007 |
Co-localization of von Willebrand factor with platelet thrombi, tissue factor and platelets with fibrin, and consistent presence of inflammatory cells in coronary thrombi obtained by an aspiration device from patients with acute myocardial infarction.
Detailed histochemical analysis of coronary thrombi obtained freshly from acute phase of myocardial infarction patients may provide information necessary to understand the mechanism of coronary occlusive thrombus formation.. Coronary thrombi causing myocardial infarction were obtained from 10 consecutive patients of myocardial infarction in the acute phase, using a newly developed aspiration catheter. All the fixed specimens of coronary thrombi, by hematoxylin and eosin staining, were found to contain three major constituents, namely, platelets, densely packed fibrin and inflammatory cells, including polymorphonuclear and mononuclear cells, although their distribution in each specimen is totally heterogeneous. Immunohistochemical staining revealed the prominent presence of von Willebrand factor (VWF) at the sites of platelet accumulation, presence of tissue factor and platelets at the sites of deposition of fibrin fibrils. It also revealed the presence of CD16-, CD45- and CD34-positive cells, yet the functional roles of these cells have still to be elucidated. There are weak positive correlation between the number of inflammatory cells involved in the unit area of coronary thrombi specimen and the time of collection of the specimens after the onset of chest pain.. In spite of various limitations, our results contain information suggesting the possible role of VWF in platelet-thrombus formation, possible important role played by tissue factor and activated platelets in the formation of fibrin fibrils, and the positive relationship between inflammatory cells migration and the formation of occlusive thrombi in human coronary arteries. Topics: Adult; Aged; Aged, 80 and over; Biopsy, Needle; Blood Platelets; Coronary Thrombosis; Female; Fibrin; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Myocardial Infarction; Thromboplastin; von Willebrand Factor | 2006 |
Differential expression of tissue factor mRNA and protein expression in murine sepsis. The role of the granulocyte revisited.
Tissue factor (TF) is a transmembrane protein, which is essential for initiation of the coagulation cascade. TF has been reported to play an important role in the progression of endotoxin (lipopolysaccharide, LPS)-mediated endotoxemia, being induced in numerous tissues, such as kidney, spleen and lung. We developed and validated a rabbit anti-murine TF peptide antiserum to localize TF protein in a murine sepsis model. TF protein distribution was compared to localization of TF mRNA and fibrin deposits, the ultimate resultant of procoagulant TF activity. Evident LPS mediated TF mRNA induction was observed in the tubular area at the cortico-medullar junction in the kidney, and TF activity was increased after 6 hours of endotoxemia. In the spleen, however, TF mRNA was induced in the interfollicular region upon LPS injection, corresponding to increased TF protein in the same area. The clusters of TF-protein positive cells in the spleen are predominantly granulocytes, but no TF mRNA expression was observed within these cells. Based on these observations and the presence of TF-protein positive granulocytes after splenectomy, we hypothesize that granulocytes take-up TF for transport to other locations in order to initiate fibrin formation or to induce pro-inflammatory gene expression upon interaction with factor VIIa. Topics: Animals; Endotoxemia; Female; Fibrin; Gene Expression Regulation; Granulocytes; Immune Sera; Inflammation; Kidney; Lipopolysaccharides; Mice; Protein Transport; Rabbits; RNA, Messenger; Sepsis; Spleen; Thromboplastin; Tissue Distribution | 2006 |
Carbon monoxide-induced early thrombolysis contributes to heme oxygenase-1-mediated inhibition of neointimal growth after vascular injury in hypercholesterolemic mice.
Arterial thrombosis is a critical event in the pathogenesis of lesion development. In this study, we evaluated the effect of heme oxygenase-1 (HO-1), a stress-inducible enzyme with vasoprotective functions, on arterial thrombosis following vascular mechanical injury. The carotid arteries of apoE-deficient mice were subjected to angioplasty with a modified beaded-needle. Arterial thrombosis occurred at 12 h after injury. Treatment of the injured vessels with an adenovirus bearing HO-1 gene (Adv-HO-1) (1 x 10(8) pfu), but not saline or empty adenovirus (Adv), immediately after angioplasty resulted in earlier thrombolysis and restoration of blood flow detected at 24 h. Immunohistochemistry revealed that the arterial plasminogen activator inhibitor-1 (PAI-1) expression was markedly reduced in Adv-HO-1-treated injured arteries as compared to control counterparts. The thrombolytic effect was also observed by exposing animals with existing arterial thrombosis to carbon monoxide (CO) (250 ppm, 2 h), a byproduct derived from heme degradation by HO-1. In parallel with less fibrin(ogen) deposition, the macrophage infiltration, monocyte chemoattractant protein-1 expression and neointimal formation assessed at 2 weeks after angioplasty were substantially reduced in injured arteries treated with Adv-HO-1. These results support a role of early thrombolysis induced by CO in HO-1-mediated protection against intimal hyperplasia after vascular injury. Topics: Animals; Apolipoproteins E; Carbon Monoxide; Carotid Artery, Common; Fibrin; Fibrinogen; Heme Oxygenase-1; Hypercholesterolemia; Inflammation; Male; Mice; Muscle Development; Muscle, Smooth, Vascular; Plasminogen Activator Inhibitor 1; Thrombosis; Transduction, Genetic | 2006 |
Delayed inflammatory responses to endotoxin in fibrinogen-deficient mice.
Severe inflammation leads to haemostatic abnormalities, such as the development of microvascular thrombi. As a result, ischaemia-related downstream organ damage can occur. The present study demonstrates that mice with a total deficiency of fibrinogen (Fg(-/-)) present with altered responses to challenge with Gram-negative lipopolysaccharide (LPS). Early survival in response to continuous LPS challenge was increased in Fg(-/-) mice and histological findings indicated that this improvement correlated with a lack of fibrin deposition in organs. Neutrophils appeared early in the lungs of challenged wild-type (WT) mice, but occurred in Fg(-/-) mice at later times. This delayed response in Fg(-/-) mice was confirmed by studies that showed a strong dependence on Fg of binding of neutrophils to endothelial cells in the presence of LPS. While cytokines were also elevated in both WT and Fg(-/-) mice, their levels were generally lower at early times in this latter group. The time course of MIP-2 expression correlated with the occurrence of pulmonary leakage after LPS challenge, which was delayed in Fg(-/-) mice. These results suggest that fibrin(ogen) plays a role as an early mediator in the cross-talk between coagulation and inflammation. Topics: Afibrinogenemia; Albumins; Animals; Antithrombin III; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Line; Cytokines; E-Selectin; Endothelial Cells; Fibrin; Fibrinogen; Inflammation; Leukocyte Count; Lipopolysaccharides; Lung; Mice; Mice, Inbred BALB C; Neutrophils; Nitric Oxide; Peptide Hydrolases; Peroxidase; Time Factors | 2006 |
The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury.
Ischemia-reperfusion (I/R) injury is associated with activation of coagulation and inflammation. Interestingly, various anticoagulants have been shown to reduce both coagulation and inflammation in animal models of kidney I/R injury. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in the coagulation cascade. The aim of this study was to investigate the effect of fondaparinux in a lethal murine model of kidney I/R injury. A murine model of kidney I/R was established. In this model, we measured activation of the coagulation cascade and induction of inflammation. Administration of fondaparinux to I/R-injured mice reduced fibrin deposition in the kidney, reduced serum creatinine levels and increased survival from 0 to 44% compared with saline-treated control mice. Fondaparinux also reduced interleukin-6 and macrophage inflammatory protein-2 expression and decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced thioglycollate-induced recruitment of neutrophils into the peritoneum and inhibited the binding of U937 cells to P-selectin in vitro. Our data suggest that fondaparinux reduces kidney I/R injury primarily by inhibiting the recruitment of neutrophils. Topics: Animals; Blood Coagulation; Cell Movement; Chemokine CXCL2; Creatine; Drug Evaluation, Preclinical; Fibrin; Fondaparinux; Inflammation; Interleukin-6; Kidney; Mice; Models, Animal; Monokines; Neutrophils; Polysaccharides; Reperfusion Injury; Survival Rate | 2005 |
Associations of fibrinogen and C-reactive protein with prevalent and incident coronary heart disease are attenuated by adjustment for confounding factors. British Women's Heart and Health Study.
A cross sectional and prospective analysis of 3,745 British women aged 60-79 years at baseline was undertaken. Among these women there were 570 prevalent cases of coronary heart disease (CHD) and 151 new cases among 12,641 person-years of follow up of women who were free of CHD at baseline. Both fibrinogen and CRP were associated with indicators of socioeconomic position in childhood and adulthood and there was a cumulative effect of socioeconomic position from across the life course. The age-adjusted odds ratio (95% confidence interval) of prevalent CHD for a 1 unit (1 g/L) increase in fibrinogen was 1.29 (1.12, 1.49); with full adjustment for all potential confounding factors this attenuated to 1.09 (0.93, 1.28). The hazards ratio for incident CHD among those free of disease at baseline was 1.28 (1.00, 1.64); with full adjustment for all potential confounding factors this attenuated to 1.09 (0.84, 1.44). Similar effects of adjustment for confounding factors were seen for the associations between CRP and both prevalent and incident CHD. By contrast, the strong positive association between smoking (an established causal risk factor for CHD) and CHD was not attenuated by adjustment for life course socioeconomic position or other risk factors. We conclude that fibrinogen and CRP predict CHD but may not be causally related to it. Topics: Age Factors; Aged; Arteriosclerosis; C-Reactive Protein; Confounding Factors, Epidemiologic; Coronary Artery Disease; Coronary Disease; Female; Fibrin; Fibrinogen; Humans; Inflammation; Middle Aged; Models, Statistical; Odds Ratio; Prospective Studies; Risk Factors; Social Class | 2005 |
Factor XIII in bronchoalveolar lavage fluid from children with chronic bronchoalveolar inflammation.
Extravascular activation of the coagulation system and consequent fibrin deposition is involved in the pathomechanism of chronic bronchoalveolar inflammatory diseases. The turnover of extravascular fibrin is attenuated by its cross-linking with activated factor XIII (FXIII).. Determination of cellular and plasmatic forms of FXIII and their correlation with D-dimer level in the bronchoalveolar lavage fluid (BALF) from healthy children and from children with bronchoalveolar inflammation.. Highly sensitive immunoassays were used for the quantitation of cellular and plasma FXIII and D-dimer in the BALF of children with recurrent wheezy bronchitis and fibrosing alveolitis. BALF was investigated for FXIII-containing cells by flow cytometry.. In the BALF of controls a low amount of the cellular form of FXIII (FXIII A2) and D-dimer were measured, while plasma FXIII (FXIII A2B2) was absent. Alveolar macrophages represented the single cell population in BALF that contained FXIII. In the BALF of both patients' groups the concentration and the total amount of FXIII A2 was significantly elevated, and plasma FXIII also appeared in the BALF of most patients. The D-dimer concentration was also elevated in the patients' groups and it correlated both with plasma FXIII and neutrophil count. These findings suggest that FXIII A2 is released from activated or injured alveolar macrophages into the bronchoalveolar lining fluid and in bronchoalveolar inflammatory diseases, FXIII A2B2 also leaks out from the capillaries. By cross-linking fibrin and inhibitors of fibrinolysis to fibrin, FXIII might be a key regulator of fibrin turnover in the extravascular compartment. Topics: Adolescent; Bronchi; Bronchitis; Bronchoalveolar Lavage Fluid; Capillaries; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Factor XIII; Factor XIII Deficiency; Factor XIIIa; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Flow Cytometry; Humans; Infant; Inflammation; Macrophages; Male; Neutrophils; Pulmonary Alveoli; Time Factors | 2005 |
An indium:calcium phosphate colloid that specifically targets fibrin.
The ability of indium to target fibrin in vitro was evaluated. The radionuclide (114m)Indium (114mIn) was prepared as a soluble and colloidal (In:In) form, as well as, a mixed indium:calcium phosphate (In:CaP) colloid. Soluble 114mIn was prepared by maintaining acid pH (50 mM HCl). Colloidal 114mIn (In:In) was prepared under slightly basic conditions (50 mM Tris-Cl, pH 7.6). The mixed In:CaP colloid was prepared by incubation of 114mIn with calcium (10 mM) and phosphate (250 microM) under slightly basic conditions (50 mM Tris-Cl, pH 7.6). To assess fibrin binding, the three 114mIn preparations were mixed with diluted human plasma (source of fibrinogen). Fibrin polymerization was initiated by addition of calcium (5 mM) and thrombin (0.5 U/ml). Following incubation (15 min, 37 degrees C), the fibrin matrix was condensed, removed from the reaction mixture, and washed briefly. Fibrin uptake of 114mIn (soluble, colloidal, or In:CaP) was determined by gamma counting. Results demonstrated that soluble 114mIn exclusively bound a plasma protein electrophoretically and immunologically identified as transferrin. Although both colloidal 114mIn and 114mIn:CaP bound fibrin, the mixed 114mIn:CaP colloid demonstrated substantially higher fibrin binding activity (about 2-fold). The target of indium binding was confirmed as fibrin due to the presence of characteristic cross-linked gamma-gamma dimers (100 kDa) and beta-monomers (58 kDa) by SDS-PAGE. 114mIn colloid and the mixed 114mIn:CaP colloid demonstrated no ability to bind fibrin's precursor, fibrinogen. 114mIn:CaP fibrin binding was associated with formation of CaP, as evidenced by its dependence on phosphate concentration. The biocompatibility of CaP including its ability to bind 114mIn and specifically target fibrin may be of potential value for diagnostic imaging studies to identify regions of occult vascular stenosis (i.e., atherosclerotic plaques, deep vein thrombosis, pulmonary embolus). Topics: Biocompatible Materials; Calcium Phosphates; Colloids; Dose-Response Relationship, Drug; Electrophoresis, Agar Gel; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrinogen; Humans; Hydrogen-Ion Concentration; Indium; Indium Radioisotopes; Inflammation; Phosphates; Protein Binding; Protein Isoforms; Thrombin; Thrombosis; Time Factors | 2005 |
Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents.
Although effective coverage of challenging coronary lesions has warranted the use of overlapping drug-eluting stents, the histopathological response to stent overlap is unknown.. The arterial reaction to overlapping Cypher or Taxus drug-eluting stents was examined in rabbits with bare metal stents, BxVelocity or Express, serving as controls. Single iliac artery balloon injury was followed by placement of 2 overlapping 3.0-mm-diameter drug-eluting stents or bare metal stents in 60 animals (mean length of overlap, 9.8+/-3.6 mm). Stented arteries were harvested at 28 and 90 days for histology. Overlapped segments exhibited delayed healing compared with proximal and distal nonoverlapping sites at 28 days. Overlapped segments in Taxus stents induced significantly more luminal heterophils/eosinophils and fibrin deposition than Cypher; peristrut giant cell infiltration, however, was more frequent in the latter. Overlapping bare metal stents also showed mild delayed healing compared with nonoverlapped segments, but not to the same extent as drug-eluting stents. Although neointimal thickness within the overlap was similar in 28- and 90-day Cypher stents, there was a significant increase with Taxus (P=0.03).. Compared with bare metal stents, drug-eluting stents further delay arterial healing and promote inflammation at sites of overlap. Taxus stents induced greater fibrin deposition, medial cell loss, heterophils/eosinophils, and late neointimal hyperplasia. Patients receiving overlapping drug-eluting stents need more frequent follow-up than patients with nonoverlapping stents. Topics: Animals; Catheterization; Drug Therapy, Combination; Fibrin; Hyperplasia; Iliac Artery; Inflammation; Paclitaxel; Rabbits; Sirolimus; Stents; Treatment Outcome; Tunica Intima; Wound Healing | 2005 |
A role for the plasminogen activator system in inflammation and neurodegeneration in the central nervous system during experimental allergic encephalomyelitis.
Early signs of inflammatory demyelination include entry of fibrin(ogen) into the central nervous system (CNS), which is normally excluded by the blood-brain barrier, and up-regulation of components of the plasminogen activator system. Using mice deficient in tissue-type plasminogen activator (tPA-/-) and urokinase plasminogen activator receptor (uPAR-/-), we investigated the involvement of the PA system on the clinical and pathological features of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. tPA-/- mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of plasminogen activator inhibitor-1. This correlated with fibrin accumulation, which co-localized with nonphosphorylated neurofilament on thickened axons in experimental allergic encephalomyelitis tissue. In contrast, uPAR-/- mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. These animals developed chronic disease as a result of steadily increased inflammation, increased levels of urokinase-type plasminogen activator (uPA), and greater degree of demyelination. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis. Topics: Animals; Axons; Central Nervous System; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Female; Fibrin; Fibrinolysis; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Nerve Degeneration; Plasminogen Activator Inhibitor 1; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator | 2005 |
Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion.
This study investigated the contribution of endogenous suppression of fibrinolysis and increased fibrin deposition to intestinal dysfunction and injury in a rat model of intestinal ischemia/reperfusion (I/R), as fibrinolytic inhibition may lead to thrombotic obstructions that compromise microcirculation and promote intestinal injury. Circulatory fibrinolysis was enhanced by intravenous administration of recombinant tissue plasminogen activator (rt-PA) or by inhibition of PAI-I by administration of MA-33H1F7. Coagulation and fibrinolysis parameters obtained from portal blood were correlated to fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance) and intestinal injury (histological evaluation by Park/Chiu score). Enhanced circulatory fibrinolytic activity, as evidenced by increased portal plasma plasminogen activator activity, elevated fibrin degradation products and decreased levels of PAI-I, did not reduce mucosal fibrin deposition and microthrombosis in postischemic intestinal tissue. Furthermore, rt-PA or anti-PAI-I antibody administration did not attenuate I/R-induced intestinal injury or dysfunction, as demonstrated by intestinal histopathology scores of 4.8+/-0.2 and 4.7+/-0.3 (control I/R group 4.7+/-0.2) and glucose clearances of 47+/-6 and 46+/-9 micro L/min g (control I/R group 30+/-8 micro L/min. g) after 40 minutes of intestinal ischemia and 3 hours of reperfusion, respectively. However, both interventions resulted in decreased levels of interleukin-6, which may indicate fibrin-induced modulation of inflammation. Attempts to enhance the fibrinolytic activity (either by rt-PA or by anti-PAI-I administration), indicated by increased portal plasma levels of released FDP, failed to decrease mucosal fibrin deposition and to attenuate intestinal I/R injury. Based on our observations and previous reports, the contribution of suppressed endogenous fibrinolysis to microcirculatory fibrin deposition and I/R-injury may be of limited importance. Topics: Animals; Biological Transport; Cytokines; Fibrin; Fibrinolysis; Immunohistochemistry; Inflammation; Interleukin-6; Male; Microcirculation; Mucous Membrane; Plasminogen Inactivators; Rats; Rats, Wistar; Recombinant Proteins; Reperfusion; Reperfusion Injury; Thrombosis; Time Factors; Tissue Plasminogen Activator; Water | 2004 |
Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress.
Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies. Topics: Animals; Animals, Newborn; Blood Coagulation Factors; Bronchopulmonary Dysplasia; Extracellular Matrix; Fibrin; Fibrinolysis; Gene Expression Profiling; Humans; Infant, Newborn; Inflammation; Lung; Oxidative Stress; Rats; Receptor, Fibroblast Growth Factor, Type 4; Receptors, Fibroblast Growth Factor; RNA, Messenger; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2 | 2004 |
Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis.
In multiple sclerosis, in which brain tissue becomes permeable to blood proteins, extravascular fibrin deposition correlates with sites of inflammatory demyelination and axonal damage. To examine the role of fibrin in neuroinflammatory demyelination, we depleted fibrin in two tumor necrosis factor transgenic mouse models of multiple sclerosis, transgenic lines TgK21 and Tg6074. In a genetic analysis, we crossed TgK21 mice into a fibrin-deficient background. TgK21fib(-/-) mice had decreased inflammation and expression of major histocompatibility complex class I antigens, reduced demyelination, and a lengthened lifespan compared with TgK21 mice. In a pharmacologic analysis, fibrin depletion, by using the snake venom ancrod, in Tg6074 mice also delayed the onset of inflammatory demyelination. Overall, these results indicate that fibrin regulates the inflammatory response in neuroinflammatory diseases. Design of therapeutic strategies based on fibrin depletion could potentially benefit the clinical course of demyelinating diseases such as multiple sclerosis. Topics: Animals; Cell Line; Demyelinating Diseases; Fibrin; Inflammation; Macrophage Activation; Mice; Mice, Transgenic; Multiple Sclerosis; Plasminogen Activators; Tumor Necrosis Factor-alpha; Up-Regulation | 2004 |
Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo.
The leukocyte integrin alpha(M)beta(2)/Mac-1 appears to support the inflammatory response through multiple ligands, but local engagement of fibrin(ogen) may be particularly important for leukocyte function. To define the biological significance of fibrin(ogen)-alpha(M)beta(2) interaction in vivo, gene-targeted mice were generated in which the alpha(M)beta(2)-binding motif within the fibrinogen gamma chain (N(390)RLSIGE(396)) was converted to a series of alanine residues. Mice carrying the Fibgamma(390-396A) allele maintained normal levels of fibrinogen, retained normal clotting function, supported platelet aggregation, and never developed spontaneous hemorrhagic events. However, the mutant fibrinogen failed to support alpha(M)beta(2)-mediated adhesion of primary neutrophils, macrophages, and alpha(M)beta(2)-expressing cell lines. The elimination of the alpha(M)beta(2)-binding motif on fibrin(ogen) severely compromised the inflammatory response in vivo as evidenced by a dramatic impediment in leukocyte clearance of Staphylococcus aureus inoculated into the peritoneal cavity. This defect in bacterial clearance was due not to diminished leukocyte trafficking but rather to a failure to fully implement antimicrobial functions. These studies definitively demonstrate that fibrin(ogen) is a physiologically relevant ligand for alpha(M)beta(2), integrin engagement of fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function. Topics: Animals; Blood Coagulation; Blood Platelets; Fibrin; Fibrinogen; Inflammation; Leukocytes; Macrophage-1 Antigen; Mice; Mutagenesis, Site-Directed | 2004 |
In vivo evaluation of a novel electrically conductive polypyrrole/poly(D,L-lactide) composite and polypyrrole-coated poly(D,L-lactide-co-glycolide) membranes.
This study evaluated the in vivo biocompatibility and biodegradation behavior of a novel polypyrrole (PPy)/poly(D,L-lactide) (PDLLA) composite and PPy-coated poly(D,L-lactide-co-glycolide) membranes. Test membranes were implanted subcutaneously in rats for 3-120 days. The biocompatibility was assessed by quantifying the alkaline and acid phosphatase secretion, the immunohistochemical staining of the ED-2-positive macrophages, and the histology at the tissue/material interface. The degradation was investigated using scanning electron microscopy. Pure PDLLA and poly(D,L-lactide-co-glycolide) membranes were used as references, whereas expanded polytetrafluoroethylene and a commercial styrene-butadiene rubber were used as controls. The enzyme activity of the PPy-containing specimens was shown to be similar to that of the references. The histological findings were consistent with the enzymatic results, showing a mild-to-moderate acute inflammation followed by a resolution of the inflammatory response with a decrease in inflammatory cells for each biodegradable membrane. The tissue reactions to the PPy, which was either in the form of nanoparticles or surface coating, were comparable to the response to the neighboring biodegradable materials. Elevated ED-2-positive macrophage populations appeared as early as day 3 in the loose connective tissue surrounding the implants. The density of these populations was related to the degree of inflammation. Scanning electron microscopy showed that the degradation of the PPy/PDLLA composite was not affected by the presence of PPy. Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Biocompatible Materials; Biodegradation, Environmental; Collagen; Electric Conductivity; Fibrin; Immunohistochemistry; Inflammation; Lactic Acid; Macrophages; Male; Materials Testing; Membranes, Artificial; Microscopy, Electron, Scanning; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Polytetrafluoroethylene; Prostheses and Implants; Pyrroles; Rats; Rats, Sprague-Dawley; Sterilization; Tissue Fixation | 2004 |
Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes.
Antiphospholipid syndrome is characterized by recurrent pregnancy loss, thrombosis, and antiphospholipid antibodies. However, some women with clinical features of antiphospholipid syndrome test negative for antiphospholipid antibodies ("antiphospholipid-like syndrome"). Women with antiphospholipid and antiphospholipid-like syndromes have serum immunoglobulin G that harms murine pregnancy, suggesting that the mechanisms of fetal death may be similar in both groups. The objective of our study was to determine whether patients with antiphospholipid and antiphospholipid-like syndromes share pathophysiology by comparing the histology of gestational tissues from these groups.. Placenta and abortion specimens were obtained from 44 pregnancies in 26 women with antiphospholipid syndrome and 37 pregnancies in 21 women with antiphospholipid-like syndrome. Of these, 16 pregnancies with antiphospholipid syndrome and 8 with antiphospholipid-like syndrome were treated with a variety of medications intended to improve pregnancy outcome. Placentas from 31 elective pregnancy terminations and 40 pregnancies complicated by idiopathic preterm delivery served as an additional control group. Twenty histologic parameters were systematically assessed by a single investigator who was blinded to the clinical status of the specimens. Histopathologic findings were compared among groups using multivariate logistic regression analysis.. Antiphospholipid syndrome pregnancies included 15 spontaneous abortions, 13 fetal deaths, and 16 live births. Pregnancies in the antiphospholipid-like syndrome group resulted in 5 spontaneous abortions, 30 fetal deaths, and one live birth. Gestational tissues from antiphospholipid and antiphospholipid-like syndrome pregnancies were similar for every histologic feature tested. Decidua from women with both antiphospholipid and antiphospholipid-like syndromes had more necrosis, acute and chronic inflammation, and vascular thrombus compared to controls. Placental tissue from antiphospholipid and antiphospholipid-like syndrome pregnancies showed more infarction, intravascular fibrin deposition, syncytial knot formation, and fibrosis than controls. Histologic features were variable within groups. There were no histologic differences in tissues from live births and pregnancy losses, or in treated and untreated pregnancies.. Placental histopathology is similar in antiphospholipid and antiphospholipid-like syndrome pregnancies, suggesting that these disorders may share pathophysiology. Histologic findings in women with APS are non-specific and may not differentiate between women with APS and APS-like syndromes. Topics: Abortion, Spontaneous; Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Chorionic Villi; Decidua; Female; Fetal Death; Fibrin; Fibrosis; Humans; Inflammation; Logistic Models; Necrosis; Placenta; Pregnancy; Thrombosis; Trophoblasts | 2004 |
Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness.
Mechanisms underlying airway hyperresponsiveness are not yet fully elucidated. One of the manifestations of airway inflammation is leakage of diverse plasma proteins into the airway lumen. They include fibrinogen and thrombin. Thrombin cleaves fibrinogen to form fibrin, a major component of thrombi. Fibrin inactivates surfactant. Surfactant on the airway surface maintains airway patency by lowering surface tension. In this study, immunohistochemically detected fibrin was seen along the luminal surface of distal airways in a patient who died of status asthmaticus and in mice with induced allergic airway inflammation. In addition, we observed altered airway fibrinolytic system protein balance consistent with promotion of fibrin deposition in mice with allergic airway inflammation. The airways of mice were exposed to aerosolized fibrinogen, thrombin, or to fibrinogen followed by thrombin. Only fibrinogen followed by thrombin resulted in airway hyperresponsiveness compared with controls. An aerosolized fibrinolytic agent, tissue-type plasminogen activator, significantly diminished airway hyperresponsiveness in mice with allergic airway inflammation. These results are consistent with the hypothesis that leakage of fibrinogen and thrombin and their accumulation on the airway surface can contribute to the pathogenesis of airway hyperresponsiveness. Topics: Animals; Bronchial Hyperreactivity; Fibrin; Fibrinogen; Fibrinolytic Agents; Humans; Inflammation; Mice; Mice, Inbred BALB C; Plasminogen Activators; Plasminogen Inactivators; Thrombin; Tissue Plasminogen Activator | 2004 |
Infection-induced modulation of m1 and m2 phenotypes in circulating monocytes: role in immune monitoring and early prognosis of sepsis.
To monitor and better understand the immunoinflammatory sequelae in sepsis and septic shock, systemic and monocyte-related cytokine responses were evaluated in baboons with experimental peritonitis induced by an E. coli-laden fibrin clot. Despite similar bacterial inocula, considerable interindividual variability in clinical manifestation and outcome of infection was observed. Because monocytes and macrophages are a key component of innate immunity, we hypothesized that early polarization of distinct activation programs in circulating monocytes that culminates in the emergence of either classically (M1) or alternatively (M2) activated monocytes may underlie the observed susceptibility or resistance to infection. To test our hypothesis, we analyzed infection-induced expression of cytokine mRNAs in monocytes isolated from surviving and dead animals. Our data show that resistance to E. coli sepsis may well be associated with a mixed M1/M2 activation state of circulating monocytes, whereas M1 phenotype appeared to be prevailing in monocytes from animals that died. Together with data on systemic cytokine responses, the latter findings indicate that morbidity and mortality of animals with gram-negative sepsis may well result from an overwhelming proinflammatory response. Collectively, our data contribute to a better understanding of cytokine networking in the immunoinflammatory response to microbial infection and suggest M1/M2 immunophenotypic profiling of readily available circulatory monocytes for early prognosis of severe infections. Topics: Animals; Cell Line; Cells, Cultured; Cytokines; DNA Primers; Endotoxins; Escherichia coli; Fibrin; Inflammation; Leukocytes, Mononuclear; Mice; Monocytes; Papio; Phenotype; Polymerase Chain Reaction; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sepsis; Time Factors | 2004 |
Lack of significant skin inflammation during elimination by apoptosis of large numbers of mouse cutaneous mast cells after cessation of treatment with stem cell factor.
We previously reported that subcutaneous (s.c.) administration of stem cell factor (SCF), the ligand for the c-Kit receptor, to the back skin of mice promotes marked local increases in the numbers of cutaneous mast cells (MCs), and that cessation of SCF treatment results in the rapid reduction of cutaneous MC populations by apoptosis. In the present study, we used the 125I-fibrin deposition assay, a very sensitive method for quantifying increased vascular permeability, to assess whether the clearance of large numbers of apoptotic MCs is associated with significant cutaneous inflammation. The s.c. injection of rrSCF164 (30 or 100 microg/kg/day) or rrSCF164-peg (polyethylene glycol-treated SCF, 30 or 100 microg/kg/day) for 23 days increased the numbers of dermal MCs at skin injection sites from 5.1+/-0.7 MCs/mm2 to 36.4+/-4.1, 34.7+/-9.7, 52.5+/-5.8, and 545+/-97 MCs/mm2, respectively. In contrast, MC numbers were markedly lower in mice that had been treated with SCF for 21 days, followed by 2 days of injection with the vehicle alone. Notably, when tested during the period of rapid reduction of skin MCs,125I-fibrin deposition in the skin was very similar to that in mice receiving continuous treatment with SCF or vehicle. We conclude that the rapid elimination of even very large populations of MCs by apoptosis, which also results in the clearance of the considerable quantities of proinflammatory products stored by these cells, does not lead to significant local cutaneous inflammatory responses. Topics: Allergens; Animals; Apoptosis; Biopsy; Fibrin; Fibrinogen; Histamine; Immunoglobulin E; Inflammation; Male; Mast Cells; Mice; Mice, Inbred C57BL; Models, Animal; Skin; Stem Cell Factor | 2004 |
Soluble fibrin, C-reactive protein, fibrinogen, factor VII, antithrombin, proteins C and S, tissue factor, D-dimer, and prothrombin fragment 1 + 2 in men with acute myocardial infarction
To evaluate the contribution of hematologic factors and long-term inflammation to the development of myocardial infarction at a young age, we measured hematologic variables, including soluble fibrin and high-sensitivity C-reactive protein, in 90 patients who had myocardial infarction and 138 controls Topics: Adult; Age Factors; Biomarkers; Fibrin; Humans; Inflammation; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Predictive Value of Tests | 2004 |
Effect of repeated thoracenteses on fluid characteristics, cytokines, and fibrinolytic activity in malignant pleural effusion.
To evaluate the effect of repeated thoracenteses on the fluid characteristics and the levels of various cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-5, IL-6, and IL-8, and of plasminogen activator inhibitor type 1 (PAI-1) and tissue type plasminogen activator in malignant pleural effusion and its clinical significance.. A prospective study.. Twenty-six patients with symptomatic and a large amount of free-flow malignant pleural effusions were studied. Thoracentesis with drainage of 500 mL of pleural fluid per day was performed for 3 continuous days (days 1 to 3). The effusion samples were collected to evaluate the changes of fluid characteristics, cytokine levels, and fibrinolytic activity. Chest ultrasonography was done on day 6 to observe the presence of fibrin strands. The result of pleurodesis was evaluated in the patients classified into groups based on chest ultrasonographic findings.. The values of TNF-alpha, PAI-1, IL-8, and neutrophil count in pleural fluid increased significantly during repeated thoracenteses in 26 patients studied. A positive correlation was found between the concentrations of TNF-alpha and PAI-1 and between the values of IL-8 and neutrophils. On day 6, fibrin strands were observed in the pleural effusion on chest ultrasonography in 11 patients (42%, fibrinous group) but were absent in the remaining 15 patients (nonfibrinous group). During repeated thoracenteses, a significant increase of effusion PAI-1 and TNF-alpha was observed in the fibrinous group but not in the nonfibrinous group. In addition, the levels of effusion PAI-1 and TNF-alpha obtained from day 2 and day 3 were significantly higher in the fibrinous group than in the nonfibrinous group. The success rate of pleurodesis was significantly higher in the fibrinous group (11 of 11 patients, 100%) than in the nonfibrinous group (8 of 12 patients, 67%).. Repeated thoracenteses may cause pleural inflammation and induce local release of proinflammatory cytokine as TNF-alpha, which may subsequently enhance the release of PAI-1 and lead to fibrin formation in malignant effusion. The presence of fibrin strands after repeated thoracenteses may be of considerable value in predicting the success of subsequent pleurodesis in patients with malignant pleural effusions. Topics: Adult; Aged; Aged, 80 and over; Cytokines; Female; Fibrin; Humans; Inflammation; Interleukins; Male; Middle Aged; Neutrophils; Paracentesis; Plasminogen Activator Inhibitor 1; Pleural Effusion, Malignant; Prospective Studies; Retreatment; Tumor Necrosis Factor-alpha | 2003 |
Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion.
Patients with Type 1 diabetes have a tighter plasma fibrin gel structure, to which impaired glycemic control might contribute. Improved glycemic control can be achieved with continuous subcutaneous insulin infusion (CSII).. The aim of the present study was to investigate the effect of CSII on plasma fibrin gel properties and circulating markers of inflammatory activity in patients with Type 1 diabetes.. Twenty-eight patients were investigated before and after 4-6 months' treatment with CSII. Fibrin gel structure formed in vitro from plasma samples was investigated by liquid permeation of hydrated fibrin gel networks. P-fibrinogen was analyzed by a syneresis method. Comparisons were made between patients with improved (> 0.5%) and unchanged (< 0.5%) glucosylated hemoglobin (HbA1c) during CSII.. Eighteen patients showed improved and 10 patients unchanged HbA1c during CSII. P-fibrinogen, high sensitive C-reactive protein and serum amyloid A-antigen were not significantly changed, while fibrin gel permeability (Ks) and fiber mass-length ratio ( micro ) increased in both groups (P < 0.02). P-insulin and triglycerides decreased (P < 0.05) in both groups, while reductions of total cholesterol and intercellular adhesion molecule-1 were seen only in patients with improved HbA(1c) (P < 0.05). Absolute changes in Ks were inversely correlated to changes in plasma fibrinogen (r = 0.50; P < 0.01) and in LDL-cholesterol (r = 0.46; P < 0.05).. Treatment with CSII in patients with Type 1 diabetes is associated with increased plasma fibrin gel porosity. Slight attenuation of the inflammatory activity was also observed. The changes in fibrin gel porosity seem to be mainly mediated by changes in plasma fibrinogen and blood lipids, and are probably secondary to improved insulin sensitivity. Topics: Adolescent; Adult; Biomarkers; Cell Adhesion Molecules; Chemokines; Cytokines; Diabetes Mellitus, Type 1; Female; Fibrin; Fibrinogen; Glycated Hemoglobin; Hematologic Tests; Humans; Inflammation; Infusions, Parenteral; Insulin; Lipids; Male; Porosity | 2003 |
Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways.
Activation of coagulation and fibrinolysis play a role in the pathophysiology of experimental arthritis.. To determine the extent of activation of the coagulation and fibrinolytic pathways in different joint diseases in humans and to ascertain the factors that may influence fibrin deposition within the joint.. Plasma from normal subjects (controls, n= 21) and plasma and synovial fluid samples from patients with rheumatoid arthritis (RA; n = 64), osteoarthritis (OA; n = 29), spondyloarthropathy (SpA; n = 22) and crystal arthritis (CA; n = 25) were analyzed for the levels of TF (tissue factor) and tissue factor pathway inhibitor (TFPI) activities, thrombin-antithrombin III (TAT) complexes, and F1 + 2 (thrombin fragment), fibrin d-dimer and thrombin-activated fibrinolysis inhibitor (TAFI) antigenic levels. The measurements were analyzed by pairwise correlation with each other as well as with standard parameters of inflammation [C-reactive protein (CRP), joint leukocyte count]. Inter-group comparisons were performed to look for disease-specific differences.. Compared with healthy controls, patients with joint diseases had higher levels of TAT, F1 + 2 and d-dimers in their plasma. In the synovial fluid, TF activity, TAT, d-dimers, and TAFI were significantly higher in inflammatory arthritides than in OA. The levels were highest in RA patients. In the plasma, TF activity was correlated with TAT and d-dimer levels with CRP, TFPI, and TAT. In the synovial fluid, TF activity correlated with plasma CRP levels, synovial fluid leukocyte count, and synovial TAT and TAFI levels. In addition, synovial d-dimers correlated with CRP, and synovial TAFI levels were correlated with synovial F1 + 2 and TAT.. Activation of the coagulation and fibrinolytic cascades in the joint and in the circulation is evident in both inflammatory and degenerative joint diseases. Within the joint, inflammatory mechanisms leading to TF-mediated activation of the coagulation pathway and subsequent fibrin deposition is the most likely explanation for the observed findings. In the plasma, the link between inflammation (CRP increase) and TF activation is weak, and a non-TF-mediated mechanism of coagulation activation could explain these findings. RA is characterized by significantly higher levels of TAT in the synovial fluid and plasma than other arthritides. Although fibrinolytic activity is linked to inflammation, the increased amounts of TAFI in the joint, particularly in RA, may explain why fibrin formation is so prominent in this condition compared with other joint diseases. Topics: Adult; Aged; Arthritis; Arthritis, Rheumatoid; Biomarkers; Blood Coagulation; Carboxypeptidase B2; Case-Control Studies; Female; Fibrin; Fibrinolysis; Humans; Inflammation; Linear Models; Male; Middle Aged; Osteoarthritis; Spondylitis, Ankylosing; Synovial Fluid | 2003 |
Tensile strength, histological and immunohistochemical observations of periodontal wound healing in the dog.
This study was designed to study wound strength at the dentine/connective tissue interface and at the bone/connective tissue interface following full thickness flap surgery. Flaps of uniform dimension were outlined in four young adult beagle dogs using a standardised double bladed knife and vertical incisions 10 mm apart, which extended 8 mm apical to the gingival margin. Bone was removed from half the sites (eight sites in each dog), giving 32 flaps replaced on dentine and 32 sites on bone. A tensile force was applied using a microprocessor force gauge at 1, 2, 3, 7, 10, 14, 21, and 28 days. Mean tensile strengths were markedly weaker for the dentine/flap interface. At 7 days the value for flaps to dentine was 1.82 N, in contrast to 5.08 N for flaps replaced on bone. Inflammatory cell counts tended to fall markedly at 3 days for both modalities, but were higher for the dentine/flap modality at all time points. Fibroblast density peaked at 7-14 days but did not vary with type of flap over the time points studied. The amounts of fibrin were greater for the dentine/flap interface at all time points but decreased for both flap types as time progressed. Collagen type V was localised to the basement membrane and blood vessels and tended to show more foci for flaps replaced on dentine. Procollagen levels showed little change over the healing interval for both flap/bone and flap/dentine interfaces. Type III collagen synthesis was at peak levels during the first week. These findings would support efforts to stabilise periodontal flaps at early time points, especially those on dentine. Topics: Alveolar Process; Alveolectomy; Animals; Basement Membrane; Blood Vessels; Cell Count; Chi-Square Distribution; Collagen Type III; Collagen Type V; Connective Tissue; Dentin; Dogs; Fibrin; Fibroblasts; Immunohistochemistry; Inflammation; Periodontal Ligament; Procollagen; Root Planing; Statistics, Nonparametric; Stress, Mechanical; Surgical Flaps; Tensile Strength; Time Factors; Wound Healing | 2002 |
Placental pathology in early onset pre-eclampsia and intra-uterine growth restriction in women with and without thrombophilia.
The incidence of placental thrombotic lesions in early onset preeclampsia (PE) and/or intrauterine growth restriction (IUGR) were compared between women with and without thrombophilia or hyperhomocysteinemia.. Matched case-control study. 183 women with a history of early onset PE and/or IUGR were tested for thrombophilia and hyperhomocysteinemia. From the 66 women with a thrombophilic factor the placental histological slides were available in 47 women. These were matched for maternal condition (PE and/or IUGR), gestational age at delivery, parity and maternal age, to 47 women with no thrombophilic factor. All slides were revised for lymphohistiocytic villitis, fetal thrombosis and fibrin depositions.. There were no significant differences between the placentas of the matched groups with and without a thrombophilic factor.. Placental thrombotic and inflammatory lesions associated with early onset PE and/or IUGR do not occur more often in women with compared to women without thrombophilia or hyperhomocysteinemia. Topics: Case-Control Studies; Female; Fetal Growth Retardation; Fibrin; Humans; Hyperhomocysteinemia; Inflammation; Placenta; Pre-Eclampsia; Pregnancy; Thrombophilia; Thrombosis | 2002 |
Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation.
A thrombotic/inflammatory reaction is elicited when isolated islets of Langerhans come in contact with ABO-compatible blood. The detrimental effects of this instant blood-mediated inflammatory reaction (IBMIR) provide a reasonable explanation for the observation that an unexpectedly high number of islets, from several donors, are needed to produce normoglycemia in transplant patients with type 1 diabetes. In this study, the hypothesis that a specific thrombin inhibitor, Melagatran, could reduce IBMIR in an in vitro model in which human islets are exposed to ABO-compatible blood was tested. The administration of Melagatran abrogated IBMIR dose-dependently. Islets exposed to blood, in the absence or presence of 0.4 micromol/l Melagatran, exhibited a loss of integrity and were found to be trapped in macroscopic clots containing platelets and CD11b(+) leukocytes. At concentrations from 1 to 10 micromol/l, Melagatran inhibited both coagulation and complement activation. Also, platelet and leukocyte activation and consumption were decreased. Islet morphology was maintained with almost no platelets adhering to the surface, and infiltration by CD11b(+) leukocytes was considerably reduced. In conclusion, Melagatran significantly reduced IBMIR in this model system. This protective effect indicates that thrombin plays a pivotal role in IBMIR and suggests that thrombin inhibition can improve the outcome of clinical islet transplantation. Topics: ABO Blood-Group System; Aged; Aged, 80 and over; Anticoagulants; Azetidines; Benzylamines; Blood Platelets; Cadaver; CD11 Antigens; Female; Fibrin; Glycine; Humans; Immunohistochemistry; Inflammation; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Neutrophils; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombin; Thrombosis | 2002 |
Mouse carotid artery ligation induces platelet-leukocyte-dependent luminal fibrin, required for neointima development.
The relationship between platelet and leukocyte activation, coagulation, and neointima development was investigated in noninjured murine blood vessels subjected to blood stasis. The left common carotid artery of C57BL/6J mice was ligated proximal to the bifurcation. Tissue-factor expression in luminal leukocytes progressively increased over 2 weeks. On day 3 after ligation, in addition to infiltrated granulocytes, platelet microthrombi and platelet-covered leukocytes as well as tissue-factor-positive fibrin deposits lined the endothelium. Maximal neointima formation in carotid artery cross sections of control mice equaled 28+/-3.7% (n=11) and 42+/-5.1% (n=8) of the internal elastic lamina cross-sectional area 1 and 2 weeks after ligation. In FVIII(-/-) mice, stenosis was significantly lower 1 (11+/-3.6%, n=8) and 2 (21+/-4.7%, n=7) weeks after ligation (both P:<0.01 versus background-matched controls). In u-PA(-/-) mice, luminal stenosis was significantly higher 1 (38+/-7.0%, n=7) and 2 (77+/-5.6%, n=6) weeks after ligation (P:<0.05 and P:<0.01, respectively, versus matched controls). In alpha(2)-AP(-/-) mice, stenosis was lower at 1 week (14+/-2.6%, n=7, P:<0.01) but not at 2 weeks. Responses in tissue-type plasminogen activator or plasminogen activator inhibitor-1 gene-deficient mice equaled that in controls. Reducing plasma fibrinogen levels in controls with ancrod or inducing partial thrombocytopenia with busulfan resulted in significantly less neointima, but inflammation was inhibited only in busulfan-treated mice. We conclude that stasis induces platelet activation, leading to microthrombosis and platelet-leukocyte conjugate formation, triggering inflammation and tissue-factor accumulation on the carotid artery endothelium. Delayed coagulation then results in formation of a fibrin matrix, which is used by smooth muscle cells to migrate into the lumen. Topics: Afibrinogenemia; Animals; Blood Coagulation; Blood Platelets; Carotid Arteries; Cell Division; Disease Models, Animal; Endothelium, Vascular; Fibrin; Hemostatic Disorders; Inflammation; Leukocytes; Ligation; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Platelet Activation; Thrombocytopenia; Thromboplastin; Thrombosis; Tunica Intima | 2001 |
Pathological analysis of local delivery of paclitaxel via a polymer-coated stent.
Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored.. Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulfate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 microgram of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 microgram of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher-dose (42.0 and 20.2 microgram) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal hemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth as uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 microgram of paclitaxel. CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days. Topics: Angiogenesis Inhibitors; Animals; Cell Division; Chondroitin Sulfates; Dose-Response Relationship, Drug; Drug Delivery Systems; Fibrin; Gelatin; Hemorrhage; Iliac Artery; Inflammation; Male; Paclitaxel; Polymers; Rabbits; Stents; Time Factors; Tunica Intima | 2001 |
Molecular basis of biomaterial-mediated foreign body reactions.
Despite being inert and nontoxic, implanted biomaterials often trigger adverse foreign body reactions such as inflammation, fibrosis, infection, and thrombosis. With regard to the inflammatory responses to biomaterial implants, it was previously found that a crucial precedent event was the spontaneous adsorption and denaturation of fibrinogen on implant surfaces. It was further found that interactions between the phagocyte integrin Mac-1 (CD11b/CD18) and one short sequence within the fibrinogen D domain (gamma 190-202; P1) at least partially explained phagocyte accumulation on implant surfaces. However, the reason that adsorbed fibrinogen is proinflammatory--while soluble fibrinogen clearly is not--remained obscure. In this study, therefore, the question of how fibrinogen is converted to a proinflammatory state when adsorbed to biomaterial surfaces is investigated. In soluble fibrinogen, the 13 amino acid P1 sequence was found to be hidden. However, the adsorption and denaturation of fibrinogen on the surfaces of commonly used biomaterials lead to the exposure of P1 and a second neo-epitope, gamma 377-395 (P2), which also interacts with Mac-1 and is similarly occult in the soluble protein. The extent of biomaterial-mediated P1 and P2 exposure appears directly related to the severity of inflammatory responses to a test panel of biomaterials. Finally, thrombin-mediated conversion of fibrinogen to fibrin also exposes both P1 and P2 epitopes. These observations may help explain both the inflammation caused by many types of implanted biomaterials and that which occurs naturally following thrombotic events. (Blood. 2001;98:1231-1238) Topics: Adsorption; Animals; Binding Sites; Biocompatible Materials; Cell Adhesion; Epitopes; Fibrin; Fibrinogen; Foreign-Body Reaction; Humans; Inflammation; Macrophage-1 Antigen; Male; Mice; Models, Animal; Phagocytes; Polyethylene Terephthalates; Protein Binding; Protein Structure, Tertiary; Thrombin | 2001 |
Extinguishing Egr-1-dependent inflammatory and thrombotic cascades after lung transplantation.
Hypoxic induction of the early growth response-1 (Egr-1) transcription factor initiates proinflammatory and procoagulant gene expression. Orthotopic/isogeneic rat lung transplantation triggers Egr-1 expression and nuclear DNA binding activity corresponding to Egr-1, which leads to increased expression of downstream target genes such as interleukin-1b, tissue factor, and plasminogen activator inhibitor-1. The devastating functional consequences of Egr-1 up-regulation in this setting are prevented by treating donor lungs with a phosphorothioate antisense oligodeoxyribonucleotide directed against the Egr-1 translation initiation site, which blocks expression of Egr-1 and its gene targets. Post-transplant graft leukostasis, inflammation, and thrombosis are consequently diminished, with marked improvement in graft function and recipient survival. Blocking expression of a proximal transcription factor, which activates deleterious inflammatory and coagulant effector mechanisms, is an effective molecular strategy to improve organ preservation. Topics: Animals; Blotting, Northern; Blotting, Western; DNA-Binding Proteins; DNA, Antisense; Early Growth Response Protein 1; Fibrin; Gene Expression; Gene Expression Regulation; Graft Survival; Immediate-Early Proteins; Inflammation; Interleukin-1; Lung Transplantation; Plasminogen Activator Inhibitor 1; Rats; RNA, Messenger; Signal Transduction; Thromboplastin; Thrombosis; Transcription Factors | 2001 |
A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin: its application to the measurement of granulocyte-derived elastase digests in plasma.
When granulocytes are stimulated under certain clinical conditions, elastase is released therefrom and digests fibrin(ogen) independently of the plasmin system, which may also be mobilized simultaneously. Thus, discrimination of these 2 systems becomes urgent for the diagnosis and treatment of the underlying diseases. Using as immunogen a 97-kd granulocyte-elastase digest of human fibrinogen, we raised an antibody IF-123 that specifically recognizes elastase digests of human fibrin(ogen). The 97-kd elastase fragment resembles plasmic fragment D(1), and the epitope of this antibody is located on the Aalpha (196-204) residue segment. This segment appears to be masked in fibrin(ogen) but exposed when the Aalpha Leu 204-Ile 205 peptide bond is cleaved by elastase. Cathepsin G concomitantly released from granulocytes failed to expose the epitope. By an enzyme immunoassay using IF-123 as the capture antibody, the elastase digests of fibrin(ogen) can be measured in plasma samples without interference by abundantly coexisting fibrinogen. Indeed, we found that the elastase digests were mostly elevated in patients with inflammation or malignant tumors, but remained in a normal range in patients with a benign gastrointestinal tract disease such as duodenal ulcer and polyps in the gallbladder or the colon. Like the plasmic D-dimer, the elastase digests predominantly consisted of the DD/E complex and DD/E-containing high-molecular weight derivatives apparently corresponding to the phase-3 plasmic digests of cross-linked fibrin. (Blood. 2000;95:1721-1728) Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Affinity; Enzyme-Linked Immunosorbent Assay; Epitopes; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Gastrointestinal Diseases; Granulocytes; Humans; Inflammation; Leukocyte Elastase; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Neoplasms | 2000 |
Potentiation of endogenous fibrinolysis and rescue from lung ischemia/reperfusion injury in interleukin (IL)-10-reconstituted IL-10 null mice.
Little is known about interactions between endogenous anti-inflammatory paradigms and microvascular thrombosis in lung ischemia/reperfusion (I/R) injury. Interleukin (IL)-10 suppresses macrophage activation and down-regulates proinflammatory cytokine production, but there are no available data to suggest a link between IL-10, thrombosis, and fibrinolysis in the setting of I/R. We hypothesized that hypoxia/ischemia triggers IL-10 production, to dampen proinflammatory cytokine and adhesion receptor cascades and to restore vascular patency by fibrinolytic potentiation. Studies were performed in a mouse lung I/R model. IL-10 mRNA levels in lung were increased 43-fold over base line by 1 h of ischemia/2 h of reperfusion, with a corresponding increase in plasma IL-10. Expression was prominently localized in bronchial epithelial cells and mononuclear phagocytes. To study the link between IL-10 and fibrinolysis in vivo, the induction of plasminogen activator inhibitor-1 (PAI-1) was evaluated. Northern analysis demonstrated exaggerated pulmonary PAI-1 expression in IL-10 (-/-) mice after I/R, with a corresponding increase in plasma PAI/tissue-type plasminogen activator activity. In vivo, IL-10 (-/-) mice showed poor postischemic lung function and survival after I/R compared with IL-10 (+/+) mice. Despite a decrease in infiltration of mononuclear phagocytes in I/R lungs of IL-10 (-/-) mice, an increased intravascular pulmonary fibrin deposition was observed by immunohistochemistry and Western blotting, along with increased IL-1 expression. Recombinant IL-10 given to IL-10 (-/-) mice normalized the PAI/tissue-type plasminogen activator ratio, reduced pulmonary vascular fibrin deposition, and rescued mice from lung injury. Since recombinant hirudin (direct thrombin inhibitor) also sufficed to rescue IL-10 (-/-) mice, these data suggest a preeminent role for microvascular thrombosis in I/R lung injury. Ischemia-driven IL-10 expression confers postischemic pulmonary protection by augmenting endogenous fibrinolytic mechanisms. Topics: Animals; Fibrin; Fibrinolysis; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-10; Ischemia; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; Reperfusion Injury; Tissue Plasminogen Activator; Transcription, Genetic | 2000 |
Renal immunofluorescence and the prediction of renal outcome in patients with proliferative lupus nephritis.
The risk for endstage renal failure in patients with proliferative lupus nephritis (PLN) depends largely on the severity and reversibility of the inflammatory process as determined by light microscopy (LM). As the intrarenal formation of immune complexes is thought to initiate this inflammation, we studied whether renal immunofluorescence microscopy (IFM) provides clinical or prognostic information in addition to LM findings. Clinical data at the time of renal biopsy and during a mean follow-up of 46 months were extracted from the records of 69 SLE patients with proliferative LN (WHO class III/IV). Biopsy specimens were analyzed by LM for AI and CI, while IFM was performed on cryostat sections with the use of antisera against IgG, IgM, IgA, C3, C1q and fibrin. IFM findings were recorded in terms of the localization (glomerular, tubular or vascular) and intensity of fluorescence (score from zero to three). IFM findings were then related to clinical and LM findings and its prognostic value studied by survival analysis. Glomerular immune deposits were present in 99% of patients, tubular deposits in 38% and vascular deposits in 17%. A 'full-house' pattern (all three Ig classes) was found in 67% of biopsies and C3 and C1q deposits in 93% and 74% respectively. Median scores for AI and CI were 6 (1-18) and 3 (0-10); aside from a negative correlation between IgA deposits and CI, we found no other correlation between the amount or type of immune deposits and AI or CI. IgM deposits were associated with high serum levels of anti-dsDNA, while IgG deposits correlated with high ESR and serum creatinin levels. IFM scores were not related to steroid dose at the time of biopsy and neither type of glomerular, tubular or overall renal immune deposits had prognostic value for renal survival. Renal immunofluorescence does not reflect light microscopy findings in patients with PLN and does not contribute prognostic information in patients with PLN. Lupus (2000) 9, 504-510. Topics: Adolescent; Adult; Complement C1q; Complement C3; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulin A; Immunoglobulin M; Inflammation; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Lupus Nephritis; Male; Microscopy, Fluorescence; Middle Aged; Predictive Value of Tests; Risk Factors; Survival Analysis | 2000 |
Purification of salmon clotting factors and their use as tissue sealants.
Fibrin sealant prepared from the blood of farmed Atlantic salmon (Salmo salar) represents a potential source of well-controlled natural material with utility in a variety of clinical settings. A potential advantage of this material is a lower probability of viral or bacterial infection that has limited general approval of fibrin glues made from human or bovine proteins. This report describes the purification of fibrinogen from salmon blood, the use of fibrin glues derived from this material to promote wound healing in rats, and the antigenic response to this material. While the low ambient temperature of these cold water fish significantly lessens the probability of infectious transmission to humans, fibrinogen and factor XIII derived from S. salar are activated by human thrombin at 25 degrees C and 37 degrees C to form clots equivalent to those formed by human fibrin. We compare the reactivity of salmon and human fibrinogen with human and bovine thrombin and the structure and viscoelastic properties of the resulting fibrin gels over a range of pH and salt concentrations. The efficacy of salmon fibrin glues in a wound healing assay and the low antigenic response to salmon fibrinogen suggest that this material may substitute for proteins derived from mammalian sources with lower probability of infections. Topics: Animals; Cattle; Elasticity; Fibrin; Fibrin Tissue Adhesive; Fibrinogen; Humans; Hydrogen-Ion Concentration; Immune Sera; Inflammation; Osmolar Concentration; Rats; Rats, Wistar; Salmon; Thrombin; Wound Healing | 2000 |
Chronic protein undernutrition and an acute inflammatory stimulus elicit different protein kinetic responses in plasma but not in muscle of piglets.
The changes in protein metabolism of severe childhood malnutrition are generally perceived as a metabolic adaptation to chronic protein undernutrition. However, severe malnutrition is invariably accompanied by infections which also have profound effects on protein metabolism. This study aimed to distinguish the effect of protein undernutrition from that of an inflammatory stimulus on muscle and plasma protein synthesis rates. Two groups of five piglets consumed diets containing either 23% or 3% protein for 4 wk. They then were infused intravenously with 2H3-leucine before and 48 h after subcutaneous injections of turpentine to measure the fractional synthesis rates (FSR) of muscle protein and both the FSR and the absolute synthesis rates (ASR) of albumin and fibrinogen. Prior to turpentine injection, compared to control piglets, protein-deficient piglets had significantly lower muscle FSR and plasma concentrations of both albumin and fibrinogen, although only albumin had lower FSR and ASR. Turpentine injection decreased muscle FSR but increased the FSR, ASR and plasma concentrations of both albumin and fibrinogen in control piglets. In protein-deficient piglets, the inflammatory stress caused a further decrease in muscle protein FSR and in plasma albumin concentration despite marked increases in albumin FSR and ASR. Fibrinogen FSR, ASR and plasma concentration were increased. We conclude that protein undernutrition and inflammation elicit the same kinetic response in muscle protein but different kinetic responses in plasma proteins. Furthermore, whereas protein deficiency reduces the plasma albumin pool via a reduction in albumin synthesis, inflammation reduces it through a stimulation of catabolism and/or loss from the intravascular space. Topics: Animals; Blood Proteins; Deuterium; Dietary Proteins; Female; Fibrin; Fibrinogen; Inflammation; Insulin; Kinetics; Male; Muscle Proteins; Muscle, Skeletal; Protein Deficiency; Serum Albumin; Swine; Turpentine; Urea | 1999 |
Accumulation of fibrinogen-coated microparticles at a fibrin(ogen)-rich inflammatory site.
We have developed methods for coating with fibrinogen both liposomes and microscopic droplets of olive oil. Because the fibrinogen bound to them is functional in the classic sense of fibrin gelation, the coated microparticles may have potential as vehicles for the targeted delivery of various molecules to sites of fibrin(ogen) deposition in vivo. So that we could assess directly this potential, we first established a method for eliciting reproducibly a focal, fibrin(ogen)-rich, inflammatory lesion in a hind footpad of mice. We then monitored the tissue distribution of fibrinogen-coated microparticles following their injection into the tail vein of mice bearing this well-defined lesion. As happens with most microparticles following their intravenous administration, liposomes and oil droplets, whether coated with fibrinogen or not, accumulate rapidly in the liver and spleen of treated animals. Indeed, in the case of oil droplets, accumulation of fibrinogen-coated microparticles in those organs and in the lungs is even greater than that of fibrinogen-free microparticles. However, as distinct from fibrinogen-free liposomes and oil droplets, fibrinogen-coated microparticles also accumulate in the inflamed hind footpad. We conclude that fibrinogen-coated liposomes and oil droplets do have potential as vehicles for delivering molecules to sites of fibrin(ogen) deposition in vivo. Topics: Adjuvants, Immunologic; Animals; Carbon Radioisotopes; Chromatography, Gel; Drug Compounding; Fibrin; Fibrinogen; Hindlimb; Inflammation; Inulin; Iodine Radioisotopes; Liposomes; Mice; Microspheres; Olive Oil; Particle Size; Plant Oils; Poloxamer; Triolein | 1999 |
Topical application of fibrin adhesive in the rat brain: effects on different cellular elements of the wound.
Although fibrin adhesives are popular in the field of neurosurgery, the medical literature is devoid of study elucidating their effects on the brain tissue. To study the safety of applying fibrin glue to the brain and to explore new surgical potentialities, we implanted soft pellets made of fibrin glue into the brains of Wistar rat. Following 6 h and 3, 7 and 14 days post-implantation survival, the brains were removed and paraffin sections were processed for hematoxylin-eosin staining, as well as immunohistochemistry for microtubule-associated protein (MAP-1A) and glial fibrillary acidic protein. The changes in the neuronal and glial elements and also the numbers of inflammatory and endothelial cells in the vicinity of implanted fibrin glue pellets were compared with those of gelfilm pellets. The results demonstrated that topical application of fibrin glue to the brain causes significantly enhanced local accumulation of mononuclear cells and promoted angiogenesis close to the wound while not affecting the neuronal and glial elements. These findings suggest that fibrin glue can be considered as a safe supportive material for intradural procedures directly involving the brain tissue. Topics: Adhesives; Animals; Astrocytes; Brain; Brain Injuries; Drug Implants; Endothelium, Vascular; Fibrin; Gelatin; Inflammation; Male; Microtubule-Associated Proteins; Neovascularization, Pathologic; Neurons; Neutrophils; Rats; Rats, Wistar | 1997 |
Collagen-coated acrylic microspheres for embolotherapy: in vivo and in vitro characteristics.
To evaluate the in vivo and in vitro properties of collagen-coated acrylic microspheres and to compare them with polyvinyl alcohol (PVA) particles.. Samples of 100- to 300-microns, 300- to 500-microns, 500- to 700-microns, and 700- to 900-microns collagen-coated acrylic microspheres and 200- to 300-microns PVA particles were suspended in solutions of 50% saline and 50% contrast material. The samples were evaluated for quantitative and qualitative microscopic characteristics (shape, size, deformability); injectability via standardized microcatheters; degree of particulate penetration in the pig rete mirabile; and reaction of tissue to the particles in 48-hour- and 4-week-old specimens.. The acrylic microspheres were spherical and deformable. The sample of 100- to 300-microns microspheres (n = 202) had a mean diameter of 210 microns (standard deviation, 43 microns). Hub accumulation, particle aggregation, and catheter occlusion were not observed with the microspheres (all sizes) but were noted with the PVA particles. The 200- to 300-microns PVA particles formed aggregates in the proximal rete. The 100- to 300-microns microspheres were found throughout the rete and beyond. Chronic transmural and perivascular inflammation was observed with the microspheres and the PVA particles.. Particle aggregation and catheter occlusion do not complicate the transcatheter delivery of collagen-coated acrylic microspheres as they do with PVA particles. For a given particle and vessel size, acrylic microspheres penetrate to a much greater extent than the PVA particles. Tissue reaction to acrylic microspheres and PVA particles is similar. Topics: Acrylic Resins; Animals; Biocompatible Materials; Blood Platelets; Carotid Artery, External; Carotid Artery, Internal; Catheterization; Collagen; Contrast Media; Embolization, Therapeutic; Equipment Design; Fibrin; Giant Cells; Inflammation; Microinjections; Microscopy; Microspheres; Neutrophils; Particle Size; Polyvinyl Alcohol; Radiography; Sodium Chloride; Surface Properties; Swine; Thrombosis; Time Factors | 1997 |
A new biological glue from gelatin and poly (L-glutamic acid).
This study describes the potentiality of hydrogels composed of gelatin and poly(L-glutamic acid) (PLGA) as a biological glue for soft tissues and compares its effectiveness with that of a conventional fibrin glue. Water-soluble carbodiimides (WSC) were used to crosslink the aqueous mixture of gelatin and PLGA. The mixed aqueous solution of gelatin and PLGA set to a hydrogel by use of WSC as rapidly as BOLHEAL fibrin glue. An addition of PLGA to gelatin aqueous solution reduced not only its gelation time but also the WSC concentration necessary for hydrogel formation. The cured hydrogel exhibited firm adhesion to the mouse skin and other soft tissues with a higher bonding strength than BOLHEAL fibrin glue. Cohesive failure in the hydrogel was observed when the gel-tissue bond was broken, in contrast to BOLHEAL fibrin glue. The bonding strength of the gelatin-PLGA hydrogel became higher with the increasing PLGA concentration. The inflammatory reaction around the gelatin-PLGA hydrogel subcutaneously implanted in mice was mild, and the hydrogel was gradually absorbed with time in vivo. A toxicity test demonstrated that the concentration of WSC necessary as a biological glue was low enough not to induce its toxicity. Topics: Adhesives; Animals; Biocompatible Materials; Biodegradation, Environmental; Carbodiimides; Cross-Linking Reagents; Drug Combinations; Female; Fibrin; Gelatin; Indicators and Reagents; Inflammation; Mice; Mice, Inbred BALB C; Polyglutamic Acid | 1996 |
Biological molecule-impregnated polyester: an in vivo angiogenesis study.
Specific extracellular matrix molecules and growth factors (GFs) with angiogenic properties could be combined with biomaterials to enhance angiogenesis and subsequently tissue ingrowth through the wall of the porous structure. In this study, composite fibrin matrices containing hyaluronic acid (HA), fibronectin (FN) and/or fibroblast growth factor-1 (FGF-1), FGF-2 and an endothelial cell growth supplement (ECGS) were adsorbed onto Dacron meshes which were then implanted subcutaneously in mice. The release from the implants and the tissue distribution of implanted GFs were determined in vivo using radiolabelled FGF-2. Angiogenesis was quantified by counting the number of capillaries present in each Dacron histological serial section. Radiolabelled GF was rapidly released from matrices and was absent from them by day 28. A very low percentage of the implanted radiolabelled GFs was found in the kidneys and livers of the animals. The number of microvessels formed within fibrin-impregnated samples was increased in the presence of HA and ECGS at 14 d and of FN and ECGS or FGF-2 at 28 d. FGF-1 had no direct effect on angiogenesis in our model. These results indicate that enhancement of vascularization within prosthesis mesh may be achieved by using fibrin as a support for angiogenic molecules such as HA, FN and FGFs. Topics: Animals; Biocompatible Materials; Drug Delivery Systems; Endothelium, Vascular; Fibrin; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Fibronectins; Hyaluronic Acid; Inflammation; Isotope Labeling; Mice; Neovascularization, Physiologic; Polyethylene Terephthalates; Prostheses and Implants; Skin | 1996 |
Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes.
Fibrin deposition is characteristic of inflammatory diseases. The monocytes is central to the inflammatory response and can affect fibrinolysis by expression of urokinase (u-PA) and plasminogen activator inhibitor types 1 and 2 (PAI-1 and PAI-2, respectively). This study examines whether thrombin, which promotes fibrin deposition, can contribute to fibrin persistence by modulating expression of proteins of the fibrinolytic system. Monocytes were isolated from human peripheral blood and analyzed for PAI-2, PAI-1, and u-PA antigens by enzyme-linked immunosorbent assay (ELISA). Monocytes responded to thrombin by increased expression of PAI-2 in a dose- and time-dependent manner, with maximal synthesis at a concentration of 1 U/mL to 10 U/mL. This trend was also evident for PAI-1, which was present at much lower levels. Thrombin and lipopolysaccharide (LPS) stimulated comparable levels of PAI-2, studied at the antigen and mRNA level. The dose effet of LPS on PAI-2 and PAI-1 was found to differ from that of thrombin. The level of u-PA was undetectable by ELISA and zymography in all samples. Thrombin stimulates PAI-2 synthesis by human monocytes, therefore creating an imbalance in the fibrinolytic system. This may contribute to persistence of fibrin, deposited during inflammation. Topics: Fibrin; Fibrinolysis; Gene Expression Regulation; Humans; Inflammation; Lipopolysaccharides; Lymphoma, Large B-Cell, Diffuse; Monocytes; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Thrombin; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator | 1995 |
[Origin of increased postoperative growth after laser surgical intervention in the peritoneal cavity--an experimental animal study].
This work deals with the localization and chronology of the appearance of tissue-plasminogen-activator (t-pa) in coagulated and vaporized peritoneal lesions. 21 female WISTAR-rats were laparotomized, similar areas of the parietal peritoneum being vaporized and coagulated. The excision of these lesions was done at seven preset time intervals from 0 to 48 hours postoperatively. The occurrence of t-pa and fibrin was shown by immunohistochemical staining of cryo- and plastic-embedded sections. The differentiation of cells was done with immuno- and enzymhistochemical techniques. The inflammatory response of vaporized lesions shows to be more intense, i.e. exsudation of more fibrin, higher amount of inflammatory cells and a strongly emphasized tendency of adhesion-formation. There is a very low amount of t-pa-reactive cells up to 12 hours postoperatively, increasing after 24 and 48 hours but staying low in relationship to the total amount of cells. In coagulated lesions there is a steady increase of t-pa-reactive cells up to 12 hours postoperatively. Adjacent undamaged peritoneal areas in both types of lesions show a significant t-pa-reactivity. The visible reactivity to t-pa can be localized almost exclusively around monocytes and peritoneal macrophages. Both types of lesions do contain closely the same number of KiM2R-reactive mononuclear cells. There is an increased number of mastcells in vaporized lesions. There is more research needed to be done on the influence of different traumatic impacts on the peritoneum in order to find a causal approach to prevention of adhesions. Right now the only causal way to minimize the incidence of iatrogenic postoperative adhesions is the use of the Semm's well known Endo-coagulation-Technique. Topics: Animals; Exudates and Transudates; Female; Fibrin; Immunohistochemistry; Inflammation; Laparotomy; Laser Coagulation; Macrophages, Peritoneal; Peritoneal Cavity; Peritoneum; Rats; Rats, Wistar; Time Factors; Tissue Adhesions; Tissue Plasminogen Activator | 1995 |
Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation.
Tissue injury is accompanied by increased vascular permeability and influx of plasma proteins including fibrinogen. Fibrinogen is converted into a fibrin matrix by procoagulants activated at the site of tissue injury and inflammation. This fibrin matrix is thought to participate early in the inflammatory response by providing a temporary protein "scaffold" for inflammatory cell adhesion and migration, and subsequent remodeling of the tissue with permanent extracellular matrix proteins such as collagen. Collagen and fibronectin have been shown to regulate the expression of inflammatory cytokines, but whether fibrin can regulate cytokine expression is not known. We hypothesized that fibrin induces the expression of the proinflammatory cytokine IL-1 beta and sought to explore mechanisms responsible for this induction. In this report, we demonstrate that fibrin stimulates human PBMCs to express IL-1 beta message and protein. We show that induction of IL-1 beta by fibrin is mediated partly by the integrin receptor CD11b/CD18 and modulated by cytoskeletal rearrangement. Fibrin also suppresses production of IL-1 receptor antagonist (IL-1ra) a non-bioactive competitor of IL-1 for IL-1Rs. We propose that injured tissues where the conditions favor coagulation and fibrin accumulation, the interaction between mononuclear cells and the newly formed fibrin matrices may elicit the production of the proinflammatory cytokine IL-1 beta. This proposal is supported by immunohistochemical studies which show the co-distribution of fibrin and IL-1 beta in granulomas in lung sections from patients with the systemic granulomatous disease, sarcoidosis. Topics: Capillary Permeability; CD18 Antigens; Cytoskeleton; Fibrin; Fibrinogen; Gene Expression Regulation; Granuloma; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Lung; Monocytes; Sarcoidosis, Pulmonary; Sialoglycoproteins | 1995 |
The inflammatory-coagulant axis in the host response to gram-negative sepsis: regulatory roles of proteins and inhibitors of tissue factor.
Reciprocal interactions between elements of the acute inflammatory response and the coagulation system play important roles in host defense homeostasis during Gram-negative bacterial sepsis. However, derangements in the regulation of the inflammatory-coagulant axis in this setting may result in progressive tissue damage and disseminated intravascular coagulation. In this article, the integrated responses in the baboon model of Escherichia coli sepsis are analyzed as a basis of understanding these response interactions in the critically ill. In particular, three topics will be reviewed. First, the role of tissue factor in mediating the coagulant response to inflammation and the role of tumor necrosis factor (TNF) in initiating and amplifying this coagulant response into a full-blown consumptive coagulopathy are defined. A second and parallel topic concerns the role played by tissue factor pathway inhibitor and other anticoagulant systems in not only regulating this coagulant response, but also in attenuating the initial inflammatory response. The third topic concerns the use of assays of enzyme inhibitor complexes composed of components of these regulatory anticoagulant systems to help define the hypercoagulable state and possibly to make an early, specific diagnosis of sepsis prior to overt failure of the hemostatic system. Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Endothelium, Vascular; Escherichia coli Infections; Fibrin; Inflammation; Lipoproteins; Papio; Sepsis; Thromboplastin; Tumor Necrosis Factor-alpha | 1994 |
Fibrin(ogen) mediates acute inflammatory responses to biomaterials.
Although "biocompatible" polymeric elastomers are generally nontoxic, nonimmunogenic, and chemically inert, implants made of these materials may trigger acute and chronic inflammatory responses. Early interactions between implants and inflammatory cells are probably mediated by a layer of host proteins on the material surface. To evaluate the importance of this protein layer, we studied acute inflammatory responses of mice to samples of polyester terephthalate film (PET) that were implanted intraperitoneally for short periods. Material preincubated with albumin is "passivated," accumulating very few adherent neutrophils or macrophages, whereas uncoated or plasma-coated PET attracts large numbers of phagocytes. Neither IgG adsorption nor surface complement activation is necessary for this acute inflammation; phagocyte accumulation on uncoated implants is normal in hypogammaglobulinemic mice and in severely hypocomplementemic mice. Rather, spontaneous adsorption of fibrinogen appears to be critical: (a) PET coated with serum or hypofibrinogenemic plasma attracts as few phagocytes as does albumin-coated material; (b) in contrast, PET preincubated with serum or hypofibrinogenemic plasma containing physiologic amounts of fibrinogen elicits "normal" phagocyte recruitment; (c) most importantly, hypofibrinogenemic mice do not mount an inflammatory response to implanted PET unless the material is coated with fibrinogen or the animals are injected with fibrinogen before implantation. Thus, spontaneous adsorption of fibrinogen appears to initiate the acute inflammatory response to an implanted polymer, suggesting an interesting nexus between two major iatrogenic effects of biomaterials: clotting and inflammation. Topics: Ancrod; Animals; Biocompatible Materials; Cell Adhesion; Chemotaxis, Leukocyte; Fibrin; Fibrinogen; Humans; In Vitro Techniques; Inflammation; Mice; Mice, Inbred BALB C; Phagocytes; Polyethylene Terephthalates | 1993 |
Histomorphological evaluation of wound healing of rabbit oviduct after microsurgical reanastomosis with the use of autologous fibrin adhesive, human fibrin adhesive or poly-glycolic acid suture.
The morphology of the healing process of microsurgical reanastomosis of the rabbit oviduct with the use of fibrin adhesive, autologous and heterologous, and conventional sutures is described. Both oviducts in 48 rabbits were cut and reanastomosis were performed. The rabbits were killed at different intervals after the operations, ranging from 2 h to 28 days, and the anastomoses were evaluated by histomorphological examination. The autologous fibrin adhesive was absorbed after a week and an uncomplicated healing was observed. Heterologous fibrin adhesive caused a granulomatous inflammation interpreted as an immune reaction of the host to the foreign protein, and conventional suturing resulted in severe tissue damage with an intensive inflammatory reaction. Topics: Animals; Capillaries; Evaluation Studies as Topic; Fallopian Tubes; Female; Fibrin; Fibroblasts; Humans; Inflammation; Microsurgery; Polyglycolic Acid; Rabbits; Regeneration; Sterilization Reversal; Sutures; Time Factors; Tissue Adhesives; Wound Healing | 1993 |
The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.
Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function. Topics: Animals; Bone Marrow Transplantation; CHO Cells; Cricetinae; Escherichia coli; Fibrin; Hematopoietic Cell Growth Factors; Inflammation; Mast Cells; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Rats; Receptors, Cell Surface; Recombinant Proteins; Signal Transduction; Stem Cell Factor; Tetradecanoylphorbol Acetate | 1992 |
Pathways of fibrin turnover of human pleural mesothelial cells in vitro.
The mesothelium contains both procoagulant and fibrinolytic activities. An imbalance between these activities could account for the abnormal fibrin turnover and pleural fibrin deposition that is characteristic of pleural inflammation. Procoagulant activity of human pleural mesothelial cells (HPMC) is in part due to tissue factor, and the prothrombinase complex can also assemble at the HPMC surface. HPMC express tissue plasminogen activator (tPA) but no detectable fibrinolytic activity in a fibrin plate assay. Inhibition of HPMC fibrinolytic activity is due, in part, to elaboration of plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) as well as antiplasmins. Synthesis of PAI-1 and PAI-2 is inhibited by actinomycin D and cyclohexamide. HPMC PAI-1 is increased by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), as is tPA release, while PAI-1 mRNA is unchanged and tPA mRNA is increased. PAI-2 release is induced by TNF-alpha and TGF-beta. Because they are a rich source of PAI-1 and PAI-2, HPMC may contribute to the high levels of these inhibitors in pleural exudates. Stimulation of HPMC by TNF-alpha or TGF-beta in vitro did not alter HPMC procoagulant activity nor the balance of elevated PAI and antiplasmins relative to PA, changes that collectively favor formation and persistence of pericellular fibrin. Topics: Base Sequence; Blood Coagulation Factors; Cells, Cultured; Cycloheximide; Dactinomycin; Epithelium; Fibrin; Fibrinolysis; Fibroblasts; Humans; Inflammation; Lung; Mesothelioma; Molecular Sequence Data; Oligonucleotide Probes; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Pleural Effusion; Prothrombin; RNA, Messenger; Tissue Plasminogen Activator; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Urokinase-Type Plasminogen Activator | 1992 |
Biocompatibility of retrograde filling materials in the ferret canine. Amalgam and IRM.
Periapical tissue response to retrograde fillings of amalgam and IRM were compared in the mandibular canine of the adult male ferret. Teeth were cleaned and shaped with a standard technique and obturated with gutta-percha. The root apex was then exposed and retrofillings were placed. The animals were grouped according to observation periods of 5, 10, and 15 weeks. At the proper time the animals were killed and the lower canine tooth along with the surrounding bone was removed. The tissue blocks were examined clinically, radiographed, and prepared for histologic examination. The clinical and radiographic examination indicated both materials to be well tolerated by periapical tissues. Microscopic examination of amalgam specimens showed a decrease in inflammation and the formation of a fibrous capsule over the 15-week period. IRM specimens showed persistent inflammation and slower healing potential. Topics: Alveolar Process; Animals; Biocompatible Materials; Collagen; Connective Tissue; Dental Amalgam; Ferrets; Fibrin; Foreign-Body Reaction; Giant Cells; Gutta-Percha; Inflammation; Male; Methylmethacrylates; Osteogenesis; Periapical Tissue; Retrograde Obturation; Root Canal Filling Materials; Root Canal Therapy; Wound Healing; Zinc Oxide-Eugenol Cement | 1992 |
Effect of local hemostatics on bone induction in rats: a comparative study of bone wax, fibrin-collagen paste, and bioerodible polyorthoester with and without gentamicin.
Local hemostatics for osseous tissue should preferably be absorbable and biocompatible and should not inhibit osteogenesis. The tissue response and effect on demineralized bone-induced heterotopic osteogenesis in the abdominal muscle of 120 male Wistar rats by different local hemostatics were evaluated by light microscopy and 85Sr uptake analyses. Non-absorbable bone wax of 88% beeswax and absorbable bovine fibrin-collagen paste both significantly inhibited osteoinduction, whereas a bioerodible polyorthoester drug delivery system with or without 4% gentamicin did not. Bone wax was not absorbed and induced a chronic foreign body reaction. Fibrin-collagen paste induced less inflammation with numerous monocytes and macrophages with engulfed material. Bioerodible polyorthoester caused a very moderate tissue reaction and was mostly resorbed at week 4. Topics: Absorption; Animals; Biocompatible Materials; Bone and Bones; Collagen; Drug Combinations; Fibrin; Gentamicins; Hemostatics; Inflammation; Male; Materials Testing; Osteogenesis; Palmitates; Polyesters; Rats; Rats, Inbred Strains; Waxes | 1992 |
Technetium-99m-labeled anti-fibrin monoclonal antibody accumulation in an inflammatory focus.
Topics: Adult; Antibodies, Monoclonal; Fibrin; Humans; Inflammation; Insect Bites and Stings; Male; Radionuclide Imaging; Technetium | 1992 |
Rat peritoneal macrophage procoagulant and fibrinolytic activities. An expression of the local inflammatory response.
1. Lysates of rat (Rattus norvegicus, Wistar strain) peritoneal macrophages selected by adherence were analysed for procoagulant activity (PCA) and plasminogen activator activity (PAA). 2. PCA is expressed following in vitro stimulation by lipopolysaccharide and in vivo (respectively 118 +/- 19.1 and 147.2 +/- 45.2 mUnits/10(6) M phi) very early after the intraperitoneal injection of thioglycollate. 3. PAA present in 24 hr thioglycollate stimulated cells (79.5 +/- 26.1 mI.U./10(6) M phi), disappears in a time dependent fashion after in vitro lipopolysaccharide stimulation. 4. Our findings indicate that rat peritoneal macrophages regulate their coagulolytic activities in a specific manner. 5. Rat peritoneal cavity may be proposed as a model for the study of inflammatory reaction with PCA and PAA as its indexes. Topics: Animals; Blood Coagulation Factors; Fibrin; In Vitro Techniques; Inflammation; Macrophages; Male; Peritoneum; Rats; Rats, Inbred Strains | 1991 |
Immunohistochemical localization of coagulation, fibrinolytic and antifibrinolytic markers in adenocarcinoma of the lung.
Extravascular coagulation and fibrinolysis are intimately involved in and modulate cancer cell growth, invasion and metastasis. Samples from resection specimens of patients with primary lung cancer (adenocarcinomas) were tested with monoclonal (MAb) and polyclonal (PAb) antibodies against various factors of the coagulation or fibrinolysis systems, or against antigens of inflammatory or proliferating cells. MAb Ki-67 specific to nuclear antigens of proliferating cells showed a distinct but variable staining of cell nuclei throughout the tumor tissue. Nests of tumor tissue stained with cytokeratin-specific antibodies (PKK1), whereas other parts were negative. Fibrin(ogen) and fibronectin were found throughout the tumor tissue stroma and in the alveolar lining, and the most densely stained areas were at the transition zone between normal and tumor tissue. Fibrinolytic system components like tissue plasminogen activators (t-PA), and urokinase (u-PA), and their inhibitors PAI-1 and PAI-2 were all studied. All specimens were negative for t-PA (except endothelial linings), whereas urokinase-specific antibodies stained loosely packed tumor cells and macrophages within the tumor stromal tissue and alveolar septa. Both PAI-1 and PAI-2 were most prominently expressed within interstitial and alveolar macrophages. A weaker staining of tumor tissue cells was demonstrated. Inflammatory cells like macrophages and T lymphocytes were located in aggregates or diffusely spread within tumor stromal tissue. The inflammatory reaction was most intense at the border between normal lung and tumor tissue. Topics: Adenocarcinoma; Antibodies; Antibodies, Monoclonal; Biomarkers; Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Fibronectins; Humans; Immunohistochemistry; Inflammation; Keratins; Ki-67 Antigen; Lung Neoplasms; Macrophages; Nuclear Proteins; Plasminogen Inactivators; T-Lymphocytes; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator | 1991 |
Ocular rosacea. A histologic and immunopathologic study.
Acne rosacea is an idiopathic dermatologic disease that frequently produces conjunctival inflammation. The authors studied the histology and immunopathology of epibulbar conjunctival biopsy specimens from eight patients with ocular rosacea and compared the findings with those from conjunctiva from 13 normal individuals. The conjunctival epithelium in ocular rosacea was attenuated and infiltrated by inflammatory cells, mainly T-helper/inducer (CD4) cells, phagocytic cells, and antigen-presenting (CD14, Mac-1) cells. The difference between the normal control group and the rosacea group in the number of mononuclear cells forming these populations was statistically significant (P less than 0.01). The substantia propria of the rosacea specimens contained large subepithelial infiltrates of chronic inflammatory cells, and in some cases frank granuloma formation was evident. There was an overall mean increase of nearly all cell types, but especially of T-helper cells in the rosacea specimens compared with the controls. Interestingly, T-helper/inducer (CD4) cells, which were outnumbered by the T-suppressor (CD8) cells in the normal conjunctival epithelium (CD4/CD8 = 0.85), outnumbered the CD8-positive cells in the rosacea specimens (CD4/CD8 = 1.6). There also was a 3.5-fold increase of the CD4/CD8 ratio in the rosacea conjunctival stroma compared with the normal specimens. The mechanism involved in rosacea conjunctival inflammation resembles a type IV hypersensitivity reaction. Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Biopsy; CD4-Positive T-Lymphocytes; Complement System Proteins; Conjunctiva; Conjunctival Diseases; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulins; Inflammation; Male; Middle Aged; Rosacea; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory | 1990 |
Artificial exudate: stimulation of cell proliferation by plasma not serum is associated with fibrinolysis.
Despite its abundance of cell culture growth factors, serum does not enhance growth of the in vivo test system, the chick chorioallantoic membrane (CAM). Previously we have also shown that fibrinogen (Kabi) and its degradation products do not display mitogenic activity on the CAM, but have now been surprised to find stimulation of DNA synthesis (up to 2.5-fold) 18 h after application of human plasma [incorporation of [3H]thymidine control mean +/- SEM 8442 +/- 1338 dpm/CAM (n = 8); test--20 199 = 3491 (n = 6); t-test P less than 0.01)]. Plasma (platelet-rich and platelet-poor) was freshly prepared by minicolumn removal of citrate at 16 degrees C; 0.3 ml aliquots of 10% human plasma were applied to the CAM and groups were fixed at various time intervals. Cross-sections were examined histologically, including immunoperoxidase studies with antihuman fibrinogen which does not cross react with chick fibrinogen, and autoradiography with [3H]thymidine. Initially, a layer of plasma was observed on the surface of the CAM. After 1 h a condensed fibrillar layer of fibrin was formed and was still present at 6 h. This was associated with increased [3H]thymidine labelling of the surface layer of the CAM. By 18 h the fibrin had disappeared, indicating that it had been lysed by the CAM, and widespread [3H]thymidine labelling was observed. No inflammatory cell infiltrate was apparent, but marked oedema developed. Oedema alone was observed in controls receiving serum or Dulbecco buffer. Both platelet-rich and platelet-free plasma gave stimulation of mitogenic activity, implying that platelet-derived growth factor is not involved in the stimulation of the CAM.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Allantois; Animals; Cell Division; Chick Embryo; Chorion; DNA Replication; Exudates and Transudates; Fibrin; Fibrinolysis; Inflammation; Plasma | 1990 |
Silicone rubber-hydrogel composites as polymeric biomaterials. I. Biological properties of the silicone rubber-p(HEMA) composite.
A composite material was prepared consisting of silicone rubber matrix and particulate lightly cross-linked poly(2-hydroxyethyl methacrylate) (p(HEMA] hydrogel. The material resembling common silicone rubber is hydrophilic and swells in water like hydrogels. The effects of the implanted composite on tissues of the living organism were tested in rats by methods assessing local acute and chronic inflammatory reactions and calcification by means of radioactive indicators and by histological examination. Results of a 6 month implant study indicated no difference in reactions of the animal body on the silicone rubber-p(HEMA) composite and a non-toxic, non-irritant pure solid p(HEMA) control. Topics: Animals; Biocompatible Materials; Collagen; Composite Resins; Fibrin; Indium Radioisotopes; Inflammation; Male; Polyhydroxyethyl Methacrylate; Prostheses and Implants; Radionuclide Imaging; Rats; Rats, Inbred Strains; Silicone Elastomers | 1990 |
Biocompatibility of elastin-fibrin material in the rat.
Biocompatibility and biodegradability of a new elastin-fibrin material were investigated in several organs and tissues of the rat. It has been demonstrated that the material was quite well tolerated in all cases, except in bone marrow. Its use is considered in several aspects of reparative or constructive surgery. Topics: Animals; Biocompatible Materials; Biodegradation, Environmental; Connective Tissue; Elastin; Fibrin; Inflammation; Materials Testing; Prostheses and Implants; Rats; Rats, Inbred Strains | 1990 |
Early tissue response to transscleral neodymium: YAG cyclophotocoagulation.
Transscleral cyclophotocoagulation was performed with a neodymium: YAG laser on five patients 24-72 hr before enucleation for a blind, painful eye. The thermal mode at 20 ms and a maximum offset between aiming and therapeutic beams were kept constant. Variable parameters evaluated were energy levels between 2 and 8 J and distance from the limbus of 0.5-3.0 mm. Because of the underlying distortion in three of the eyes, meaningful interpretation by light microscopic evaluation was possible only in the other two. This suggested that the early histologic hallmark of the procedure is similar to that previously observed in human autopsy eyes with ciliary epithelial damage and elevation from underlying tissue. In addition, fibrin and scant inflammatory cells were seen in the space between ciliary epithelium and stroma. Minimal damage was observed in the ciliary muscle. These findings suggest that direct damage to the ciliary epithelium is the most likely mechanism of reduced aqueous production by this cyclodestructive procedure. The findings also support the concept that an anterior placement of approximately 1.0-1.5 mm posterior to the limbus is most likely to damage the ciliary epithelium of the pars plicata. Topics: Ciliary Body; Diabetic Retinopathy; Epithelium; Eye Enucleation; Fibrin; Glaucoma, Neovascular; Glaucoma, Open-Angle; Humans; Inflammation; Leukocytes; Light Coagulation; Sclera | 1990 |
Acute phase reaction, fibrinogen level and thrombus size.
The influence of an acute phase reaction on the size, weight, and fibrin content of experimental venous thrombi was examined in 10 pairs of rabbits. Jugular vein thrombosis was provoked by venous stasis plus mechanical injury 36 hours after one member of each pair received 0.5 ml/kg sterile turpentine in olive oil by subcutaneous injection. Fibrinogen level, factor VIII activity, and antithrombin III activity were significantly higher at the time of thrombus formation in turpentine treated rabbits, as were thrombus size (assessed by visual scoring), dry weight of thrombi, and their fibrin content (derived by measuring 125I-fibrinogen incorporation). In addition, the fibrinogen concentration correlated significantly with size, weight, and fibrin content of thrombi when results from turpentine treated and control animals were pooled, suggesting that plasma fibrinogen concentration at the time of thrombus formation may strongly influence the extent of thrombosis. This effect could help explain observations of a "hypercoagulable state" after injury. Topics: Acute-Phase Reaction; Animals; Antithrombin III; Factor VIII; Fibrin; Fibrinogen; Inflammation; Rabbits; Thrombophlebitis; Turpentine | 1989 |
Oxidized fibrin(ogen) derivatives enhance the activity of tissue type plasminogen activator.
Oxidation of fibrinogen degradation products (FDP) with chloramines, results in a five- fold increase of their property to stimulate plasminogen activation by tissue type plasminogen activator (t-PA). Binding studies with immobilized stimulators demonstrated greater affinity of t-PA to oxidized than to unmodified FDP. The fibrin (ogen) domain responsible for this oxidant mediated increase in t-PA stimulation is localized in the D- subunit of fibrin(ogen). Thus, experimental data with (oxidized) I-labelled fibrin(ogen) should be interpreted with caution: the oxidized product might behave in a distinct manner than the unoxidized, native, one. As activated leukocytes release large amounts of oxidants of the chloramine type (Weiss et al., Science 222, 625-628, 1983), oxidation of fibrin might contribute significantly to fibrinolysis and proteolysis in areas of inflammation. The data give further evidence for an involvement of physiological components of haemostasis in non haemostasis but inflammation related processes. Topics: Chloramines; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Free Radicals; Humans; In Vitro Techniques; Inflammation; Leukocytes; Oxidation-Reduction; Oxygen; Tissue Plasminogen Activator | 1989 |
Irritation effects of residual products derived from p(HEMA) gels. II. Compounds extracted from hydrogels.
Samples of poly(2-hydroxyethyl methacrylate) p(HEMA) hydrogels were prepared using three different polymerization initiators. The gels were washed in water under standard conditions. The extracts were then examined for intradermal irritation in rats using a radioactive indicator (113mIn). The irritation effects were dependent on the concentrations of the irritating substances and also on the gel type. Solid discs made of the gels, washed to varying degrees of purity, were also implanted into rats. Tissue irritation, as well as some other biological responses, were followed in situ using the radioindicator and common histological techniques. The irritation effects were very mild (even with the unextracted gel material). A possible explanation for the events taking place at the site of implantation is presented. Topics: Animals; Biocompatible Materials; Blood Proteins; Exudates and Transudates; Fibrin; Indium Radioisotopes; Inflammation; Irritants; Male; Polyhydroxyethyl Methacrylate; Polymethacrylic Acids; Prostheses and Implants; Rats; Rats, Inbred Strains; Skin | 1988 |
Local ocular hypothermia in experimental intraocular surgery.
Local ocular hypothermia was evaluated in experimental open sky vitrectomy, closed vitrectomy, and anterior chamber irrigation and aspiration in 40 albino rabbits (80 eyes). The irrigating balanced salt solution was used at room temperature in control eyes and was cooled to 7 degrees C in experimental eyes. Experimental eyes demonstrated less intraocular bleeding volume, less fibrin production, and less postoperative inflammation. No detectable tissue intolerance to hypothermia was observed on short- or long-term follow-up. Topics: Animals; Anterior Chamber; Eye Hemorrhage; Fibrin; Hypothermia, Induced; Inflammation; Postoperative Complications; Rabbits; Retinal Diseases; Retinal Hemorrhage; Vitrectomy | 1988 |
Glomerular procoagulant activity and glomerulonephritis.
Topics: Animals; Anticoagulants; Fibrin; Glomerulonephritis; Humans; Inflammation; Macrophages; Microcirculation; Monocytes; Rabbits; Rats; Thromboplastin | 1987 |
The inflammatory component of mechanical back problems.
Topics: Animals; Arachnoiditis; Back Pain; Fibrin; Humans; Inflammation; Intervertebral Disc Displacement; Radiculopathy | 1986 |
Scanning electron microscopy of antigen induced arthritic joints. I. Inflammatory cell interactions at synovial-meniscal surfaces during the Arthus response.
Scanning electron microscopy has been used to study experimental antigen induced arthritis, providing a unique perspective of the early inflammatory events. An initial aggregation of acute inflammatory cells was noted at the synovial-meniscal junction with maximal numbers observed between 12 and 24 h post challenge. Variations in cell surface ruffling, which may represent different phases of activation, were observed throughout the Arthus response. By 48 h post challenge the meniscal and synovial surfaces were covered by a mat of fibrin and degraded cell remnants. Topics: Animals; Arthus Reaction; Cell Membrane; Female; Fibrin; Immunization; Inflammation; Male; Menisci, Tibial; Microscopy, Electron, Scanning; Neutrophils; Rabbits; Serum Albumin, Bovine; Synovial Membrane; Synovitis | 1986 |
A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing.
A model is presented outlining the molecular and cellular events that occur during the early stages of the wound healing process. The underlying theme is that there is a specific binding interaction between fibrin, the major clot protein, and hyaluronic acid (HA), a constituent of the wound extracellular matrix. This binding interaction, which could also be stabilized by other cross-linking components, provides the driving force to organize a three-dimensional HA matrix attached to and interdigitated with the initial fibrin matrix. The HA-fibrin matrix plays a major role in the subsequent tissue reconstruction processes. We suggest that HA and fibrin have both structural and regulatory functions at different times during the wound healing process. The concentration of HA in blood and in the initial clot is very low. This is consistent with the proposed interaction between HA and fibrin(ogen), which could interfere with either fibrinogen activation or fibrin assembly and cross-linking. We propose that an activator (e.g. derived from a plasma precursor, platelets or surrounding cells) is produced during the clotting reaction and then stimulates one or more blood cell types to synthesize and secrete HA into the fibrin matrix of the clot. We predict that HA controls the stability of the matrix by regulating the degradation of fibrin. The new HA-fibrin matrix increases or stabilizes the volume and porosity of the clot and then serves as a physical support, a scaffold through which cells trapped in the clot or cells infiltrating from the peripheral edge of the wound can migrate. The HA-fibrin matrix also actively stimulates or induces cell motility and activates and regulates many functions of blood cells, which are involved in the inflammatory response, including phagocytosis and chemotaxis. The secondary HA-fibrin matrix itself is then modified as cells continue to migrate into the wound, secreting hyaluronidase and plasminogen activator to degrade the HA and fibrin. At the same time these cells secrete collagen and glycosaminoglycans to make a more differentiated matrix. The degradation products derived from both fibrin and HA are, in turn, important regulatory molecules which control cellular functions involved in the inflammatory response and new blood vessel formation in the healing wound. The proposed model generates a number of testable experimental predictions. Topics: Blood Coagulation; Cell Movement; Fibrin; Humans; Hyaluronic Acid; Inflammation; Models, Biological; Wound Healing | 1986 |
The course of inflammation exemplified in the synovial membrane. Personal studies and literature data.
Owing to special reactivity anchored in its structure the connective tissue responds to all kinds of injuries with tissue changes which in their completeness are designated as inflammation. An expressive carrier of mesodermal inflammation is the synovial membrane in which these tissue changes are manifested at first by the vessels and cells of the blood, and subsequently by all other constituents of the synovial membrane. Topics: Collagen; Fibrin; Fibroblasts; Humans; Hypertrophy; Inflammation; Necrosis; Synovial Membrane; Synovitis; Time Factors | 1986 |
Macrophage migration in fibrin gel matrices.
Macrophage migration has been extensively studied in vitro on artificial substrates but in vivo macrophages migrate through connective tissue and fibrin gel meshworks that comprise the stroma of many inflammatory reactions and solid tumors. Studies were therefore undertaken to investigate macrophage migration in this more biologically relevant matrix cast either with or without nitrocellulose filter support. Macrophage migration in fibrin gels depended on both fibrin and thrombin concentrations and on the nature of fibrin crosslinking. With gamma-chain crosslinking only, macrophage migration was enhanced as compared with untreated filters at fibrin concentrations of up to 5 mg/ml. However, when fibrin alpha-chains were also crosslinked, as occurs in vivo, macrophage migration was inhibited at approximately 3 mg/ml fibrin and was stopped altogether at 5 mg/ml. Thrombin concentrations of 1 unit/ml favored maximal macrophage migration. Depletion of contaminating fibronectin did not affect these results. The pore size of fibrin gels is well below the minimum that permits macrophage migration through nitrocellulose filters. Thus, to penetrate fibrin gels, macrophages could enlarge effective pore size by local fibrinolysis or by pushing apart fibrin strands. If fibrinolysis is responsible, this process must be highly localized because only small amounts of fibrinolysis accompanied extensive macrophage migration in fibrin gels; moreover, fibrinolysis inhibitors did not affect macrophage migration. We conclude that the fibrin deposited in inflammatory reactions and solid tumors is present in forms and concentrations that either facilitate or inhibit macrophage migration; fibrin may therefore regulate macrophage participation in these and other pathologic reactions. Topics: Animals; Cell Movement; Chemotaxis; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrinolysis; Filtration; Gels; Guinea Pigs; Humans; Inflammation; Macrophages; Microscopy, Electron; Thrombin | 1986 |
Abnormalities in pathways of alveolar fibrin turnover among patients with interstitial lung disease.
Fibrin deposition is prominent in the histopathologic features of chronic interstitial lung disease. Human alveolar macrophages can potentially modulate this process because normal macrophages synthesize and express the initial enzymes of both coagulation and fibrinolytic pathways. In the present study, we examined the cell-associated procoagulant activity of macrophages lavaged from patients with sarcoidosis (n = 14) or idiopathic pulmonary fibrosis (n = 13) and compared the enzyme activities with that of a group of normal volunteers (n = 16). Cells from sarcoid patients had a mean (+/- 1 SD) tissue factor activity of 1,491 +/- 2,160 units/5 X 10(5) cells, as compared with a mean of 480 units (range, 140 to 1,000 units) for normal control subjects. The same cells had a mean plasma Factor VII equivalent of 4.7 ng/10(6) cells, as compared with 0.81 ng/10(6) cells (range, 0.2 to 2.0 ng) for the normal control subjects. The enhanced activity correlated with disease activity as judged by radiographic stage: only patients with Stage II or Stage III disease had consistently elevated procoagulant activity. There was no correlation of procoagulant activity with the percentage of lymphocytes in the alveolar fluid. Cells from patients with idiopathic pulmonary fibrosis also had increased tissue factor (mean, 2,980 +/- 2,619 units) but less consistently elevated Factor VII. There was considerable variation in both procoagulant activity and cell differentials between lavage sites in 10 patients in whom 2 separate lobes were studied concurrently. In addition, we examined the plasminogen activator (PA) activities of lavaged cells and concentrated alveolar fluids.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Adult; Aged; Factor VII; Female; Fibrin; Fibrinolysis; Humans; Inflammation; Macrophages; Male; Middle Aged; Plasminogen Activators; Pulmonary Alveoli; Pulmonary Fibrosis; Sarcoidosis; Thromboplastin | 1986 |
Serum crosslinked fibrin (XDP) and fibrinogen/fibrin degradation products (FDP) in disorders associated with activation of the coagulation or fibrinolytic systems.
Soluble crosslinked fibrin derivatives (XDP) in serum were determined by enzyme immunoassay utilizing monoclonal antibodies and compared with serum fibrinogen/fibrin degradation products (FDP) assayed by conventional techniques. In healthy subjects and patients with miscellaneous disorders not usually associated with activation of the haemostasis mechanism, mean XDP levels were 45 and 70 ng/ml respectively. However, elevated levels of XDP occurred in conditions commonly associated with intravascular and possibly extravascular activation of the coagulation system. Markedly raised mean XDP values (677-6900 ng/ml) occurred in treated pulmonary embolism, disseminated neoplasia, severe inflammatory disorders and complicated postoperative states, and lesser but significant elevation (mean 150-400 ng/ml) in treated venous thrombosis, uneventful postsurgical states, localized neoplasia, liver disease and symptomatic arterial disease. Levels during initial streptokinase therapy (mean 24 000 ng/ml) fell tenfold as treatment was continued. The degree of XDP elevation over normal values was significantly higher than that of FDP in conditions with a propensity for venous thrombosis (post-operative states, disseminated neoplasia and inflammatory diseases) than in liver disease, localized neoplasia or patients receiving heparin therapy for venous thromboembolism. Topics: Adult; Aged; Antibodies, Monoclonal; Blood Coagulation; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Immunoenzyme Techniques; Inflammation; Liver Diseases; Middle Aged; Neoplasms; Streptokinase; Thromboembolism; Vascular Diseases | 1985 |
Macrophage-induced glomerular fibrin deposition in experimental glomerulonephritis in the rabbit.
Glomerular fibrin deposition is important in the pathogenesis of renal failure and crescent formation in glomerulonephritis. The mechanisms of glomerular fibrin deposition are unknown. The current studies explored the role of macrophages in this process. Methods were developed for measuring glomerular fibrin deposition and glomerular procoagulant activity in a passive model of the autologous phase of antiglomerular basement membrane antibody-induced glomerulonephritis in rabbits. Significant fibrin deposition was observed to be associated with glomerular macrophage accumulation. Leukocyte ablation with mustine hydrochloride prevented both glomerular macrophage accumulation and fibrin deposition without affecting the coagulation system or the deposition of disease-inducing antibodies and complement. Repletion with mononuclear inflammatory cells produced significant fibrin deposition. To examine the role of tissue injury per se in glomerular fibrin deposition, a macrophage-independent model of glomerular injury (heterologous phase glomerulonephritis) was also studied. Although a similar degree of glomerular injury occurred, there was no significant fibrin deposition. This suggests that macrophages, rather than injury alone, are responsible for fibrin deposition. Lysates of isolated glomeruli containing macrophages demonstrated greatly enhanced procoagulant activity compared with lysates of glomeruli without macrophages. Thus macrophages appear to be directly responsible for glomerular fibrin deposition in antiglomerular basement membrane antibody-induced glomerulonephritis, and this appears to be due to their ability to express procoagulant activity rather than their propensity to cause glomerular injury. Topics: Animals; Basement Membrane; Blood Coagulation Tests; Disease Models, Animal; Fibrin; Glomerulonephritis; Immunization, Passive; Inflammation; Kidney Glomerulus; Lymphocyte Depletion; Macrophages; Mechlorethamine; Monocytes; Rabbits; Serum Sickness | 1985 |
Macrophage metabolism of fibrin: role of fibronectin.
Topics: Animals; Blood Coagulation; Cell Membrane; Fibrin; Fibrinogen; Fibronectins; Humans; In Vitro Techniques; Inflammation; Macrophages; Monocytes; Rabbits | 1984 |
Morphology of experimental actinomycotic abscess in mice with Dermatophilus-like microorganisms from porcine tonsil.
Experimental infection in mice with Dermatophilus (D.) congolensis-like microorganisms was carried out, intraperitoneally and subcutaneously. This strain had been isolated from porcine tonsil and reported to be different in some morphological and biological points from D. congolensis. Macroscopic examination revealed multiple abscesses in the peritoneal cavities, or subcutaneous abscesses after the intraperitoneal or subcutaneous injection respectively. Histopathologic examination revealed the characteristic arrangement of the neutrophils surrounding the bacterial colony and peripheral macrophages in the abscess lesions. The lesions contained many microorganisms which showed wide range of the characteristic morphologic variation such as: mycelial elements, coccoid elements and large coccoid elements with transverse or longitudinal septa. Chlamydospore-like elements were sometimes found in the microcolonies in early lesions. The morphology of the lesions and the microorganisms was compared with those of other bacteria including D. congolensis. Topics: Abscess; Actinomycetales; Actinomycetales Infections; Animals; Fibrin; Granuloma; Inflammation; Liver Abscess; Macrophages; Mice; Necrosis; Neutrophils; Palatine Tonsil; Pancreatic Diseases; Peritoneal Cavity; Splenic Diseases; Swine | 1983 |
The Shwartzman phenomenon in equine species.
The occurrence of the Local Shwartzman Reaction (LSR) in equine species has not previously been reported. The molecular mechanism appears identical to that reported for the rabbit and other species. The immunopathologic and histopathologic similarities of the experimentally induced LSR in horses and ponies to that of the hoof-laminae (an extension of the skin) lesion in naturally-occurring and/or carbohydrate induced laminitis may offer insight into the pathogenesis of this complex disease. Topics: Animals; Blood Platelets; Endotoxins; Female; Fibrin; Fluorescent Antibody Technique; Horses; Inflammation; Male; Necrosis; Neutrophils; Shwartzman Phenomenon; Skin | 1982 |
Bullous pemphigoid, an ultrastructural study of the inflammatory response: eosinophil, basophil and mast cell granule changes in multiple biopsies from one patient.
We have studied by electron and light microscopy the inflammatory reaction in lesions at various stages of clinical development from a patient with bullous pemphigoid. The evolution of clinical lesions was associated with a sequence of histopathologic events which began with alterations of mast cells and proceeded to infiltration, first with lymphocytes and later with eosinophils and basophils. Mast cells in the papillary and reticular dermis demonstrated a unique, focal, irregular loss of granule contents. Intact eosinophils demonstrated intracytoplasmic losses of granule contents and karyorrhectic and karyolytic eosinophils had released membranebound granules. Partially and completely degranulated basophils were present within a fibrin gel which formed in the dermis. Thus, the sequence of histopathologic events in the pathogenesis of bullous pemphigoid includes mast cell granule alterations and release of granule contents from eosinophils which are undergoing nuclear and cytoplasmic damage. Topics: Basophils; Cytoplasmic Granules; Eosinophils; Fibrin; Humans; Inflammation; Macrophages; Mast Cells; Pemphigoid, Bullous; Skin; Skin Diseases, Vesiculobullous | 1982 |
High resolution light microscopy in renal pathology.
Seven hundred renal specimens embedded in epoxy resins and stained with polychromatic stains were compared with paraffin sections stained with Hematoxylin and Eosin (H & E), Perodic and Schiff, (PAS), silver, and trichrome stains. High resolution of light microscopy, never in wax histopathology, may be obtained by the use of plastic embedding and polychromatic stains. Cell boundaries, intracellular organelles, basement membranes, different cellular types, apposition of different substances, and other pathologic changes were readily recognized in a single P + P (Plastic section stained with Polychromatic stains) section, whereas paraffin sections usually needed special stains. The same plastic block may be used for transmission electron microscopy. Slightly elevated cost, special training of the technician and pathologist, and some few remaining technical difficulties are the disadvantages of this method. High resolution light microscopy methods are recommended for routine renal biopsies. Topics: Basement Membrane; Blood Vessels; Endothelium; Epithelium; Fibrin; Foam Cells; Histological Techniques; Humans; Immunoglobulins; Inflammation; Kidney; Kidney Glomerulus; Kidney Tubules; Microscopy | 1981 |
Role of splenic red pulp in endotoxin-induced disseminated intravascular coagulation.
As an extension of our studies on vascular responses to endotoxemia, we evaluated sequential ultrastructural lesions of splenic red pulp and correlated these lesions with coagulation changes observed in rhesus monkeys following infusion with endotoxin either as a single bolus (10 mg. per kg.) or at a continuous rate of 10 mg. per kg. per hour for periods up to 16 hours. Controls included monkeys infused with Ringer's lactate solution. Progressive reactions of the splenic cords included increased phagocytic activity of macrophages in association with aggregation and degranulation of platelets and prominent fibrinous deposits characteristically abutting basement membranes of endothelial and reticular cells. The sinuses demonstrated endothelial damage, platelet-fibrin microthrombi obstructing interendothelial slits, and severe engorgement with entrapment of erythrocytes by tactoids of fibrin. The thrombotic lesions of the red pulp developed earlier than similar lesions in hepatic sinusoids, and they were accompanied by progressive thrombocytopenia and disseminated intravascular coagulation. The findings suggest that the unique microcirculation of the spleen is an early target and trigger of endotoxin-induced microthrombosis. It is proposed that phagocytosis of endotoxin by splenic phagocytic cells and associated inflammatory events result in disruption of reticular cells and endothelium leading to massive microthrombosis with breakdown of the splenic filter. In addition, rapid activation of coagulation mechanisms in the red pulp as well as liver sinusoids may promote the development of thrombocytopenia and disseminated intravascular coagulation in endotoxic shock. Topics: Animals; Blood Pressure; Disseminated Intravascular Coagulation; Endotoxins; Factor XII Deficiency; Fibrin; Inflammation; Leukopenia; Macaca mulatta; Macrophages; Male; Platelet Aggregation; Spleen; Thrombosis | 1981 |
Microclot generation (MCG) test in disease. Preliminary report.
Heparinized blood was taken up into capillary tubes and kept in vertical position at 37 degrees C for 24 hours to allow the red cells to sediment. Microclots appearing as radiant fibrin stars were seen under phase microscopy in the plasma portion of blood from certain patients. Such a positive microclot generation (MCG) test occurred in patients with some inflammatory diseases and cancer as well as in patients with certain skin disorders. The data suggest that the MCG test may serve in the detection of endotoxemia. Topics: Blood Sedimentation; Crystallization; Endotoxins; Female; Fibrin; Humans; Inflammation; Male; Neoplasms; Pregnancy; Skin Diseases | 1981 |
Lung inflammation induced by complement-derived chemotactic fragments in the alveolus.
The intratracheal injection into rabbits of low molecular weight C5-derived chemotactic fragments (C5fr), prepared from zymosan-activated serum, induced an acute pulmonary inflammation characterized by intraalveolar accumulation of neutrophils, erythrocytes, and edema fluid. In separate experiments, depletion of circulating pulmonary neutrophils and absorption of C5fr with immobilized antibody to homogenous human C5a prevented the observed inflammatory changes, indicating a requirement for these two elements in initiating this reaction. When examined by transmission and scanning electron microscopy, lungs of C5fr-injected rabbits revealed pulmonary neutrophils, often appearing partially degranulated, in alveolar, pulmonary capillary, and interstitial spaces. Alveolar spaces and, less often, the interstitial compartment contained fibrinoid deposits with leukocytes and erythrocytes enmeshed in the fibrin strands. Injury to the pulmonary vascular endothelium consisted of bleb formation in capillaries and endothelial basement membrane separation with subendothelial accumulation of inflammatory cells in venules. Type I, but not type II, epithelial cell damage included blebbing and epithelial cell basement membrane detachment. Endothelial and epithelial layer damage was always associated with pulmonary neutrophils continguous to the injured structures. These studies indicate the potential for alveolar epithelial and capillary injury in neutrophil-associated pulmonary inflammation resulting from intraalveolar accumulation of chemotactic substances. Topics: Animals; Chemotaxis, Leukocyte; Complement C5; Edema; Female; Fibrin; Hemorrhage; Inflammation; Lung; Lung Diseases; Male; Microscopy, Electron, Scanning; Neutrophils; Rabbits | 1980 |
Fibrin in fibroblast cultures--a metabolic study as a contribution to inflammation and tissue repair.
Embryonic rat fibroblasts were cultured in the presence of fibrin under fibrinolytic and fibrinostatic conditions both in proliferating and confluent stages. The proliferation rate, glucose consumption, glycosaminoglycan contents and distribution pattern were determined. Additionally the influence on rat fibroblast cultures of fibrinogen and its splitting products were reinvestigated. Basing on the experimental results and a literature survey the role of fibrin in chronic inflammation was emphasized. Experimental results: 1. First step of tissue injury was simulated by formation of fibrin above a confluent fibroblast monolayer. The small degree of fibrinolysis with the cultures was sufficient to prevent all metabolic changes except a decrease of sulfate incorporation (immediately reversibly injury). Inhibition of fibrinolysis resulted in a decrease of proliferation and HA contents additionally, but in an increase of total GAG concentration and SO4-GAG. This behaviour continued during the beginning of cell proliferation. 2. The following step of fibrin contraction, improvement of nutrient supply, and cell proliferation was artificially achieved by growing non-confluent cells on the preformed fibrin network. Fibrin enhanced the cell proliferation, total GAG concentration, HA, and the turnover of SO4-GAG (sulfate incorporation). In rapidly proliferating cultures no influence of anti-fibrinolytic agents was observed. 3. On the preformed, partially contracted fibrin the cells grew to confluence: a) Without inhibition of the fibrinolysis, the parameters of the fibrin-free controls were obtained; repair seems to be completed. b) When fibrinolysis was inhibited the cells continued proliferating apparently with a tendency of enhanced HA and decreased SO4-GAG (a stage of "chronic inflammation"). 4. Purified fibrin fractions as well as the supernatant of fibrin containing fibrinopeptides were shown to advance cell proliferation. Topics: 4-Aminobenzoic Acid; Animals; Cell Division; Cell Line; Fibrin; Fibrinogen; Fibrinolysis; Fibroblasts; Glucose; Glycosaminoglycans; Humans; Inflammation; Rats; Sulfates | 1979 |
Pulmonary sequelae of acute Legionnaires' disease pneumonia.
Patients with acute Legionnaires' disease (LD) pneumonia may have persistent chronic pulmonary changes, as shown by the histologic appearance of specimens of lung from patients who had survived and autopsy specimens from patients who died after a protracted clinical course. Acute pneumonia was not seen in these lungs, and LD organisms could not be identified by the direct fluorescent antibody technique or the Dieterle silver impregnation strain; instead, there was organizing pneumonia with various degrees of interstitial inflammation and fibrosis. The LD pneumonia may fail to resolve, and the lung parenchyma in areas of previous acute inflammation is not restored to normal in some patients. Topics: Adult; Female; Fibrin; Humans; Inflammation; Legionnaires' Disease; Lung; Male; Middle Aged; Pulmonary Fibrosis | 1979 |
Leukocyte migration inhibition activity of nonimmune acute inflammatory pleural exudate.
Material with leuckocyte migration inhibition (LMI) activity has been demonstrated in various types of nonimmunologically induced acute pleural inflammatory exudates. This activity is present in inflammatory cell-free exudate and appears to involved the deposition of fibrin around the migrating leukocyte, resulting in "cell-trapping." This is supported by the fact that removal or inhibition of fibrin formation leads to loss of exudate LMI activity. Both fibrinogen and complement as well as vitamin K-dependent clotting factors appear to be required for LMI activity. The mechanism involved in the LMI reaction and its significance in nonimmune and cell-mediated immune inflammation are discussed. Topics: Animals; Cell Migration Inhibition; Fibrin; Heparin; Hot Temperature; Hydroxyapatites; Inflammation; Irritants; Leukocytes; Male; Pleural Effusion; Rats; Thrombin; Warfarin; Zymosan | 1979 |
[In vitro studies to elucidate the fibrinolytic activity in cerebrospinal fluid altered by inflammation and hemorrhage and having pathologic protein values].
Using selectively immunological methods, it was possible, through FSP determination, for plasmin activities and plasminogen concentrations to be occasionally and exclusively detected in inflammatorily altered liquores and in bloody liquores, respectively. Thus, bloody cerebrospinal fluid, in contrast with inflammatorily altered liquor, usually shows free fibrinolytic activity, so that antifibrinolytic therapy of intracranial aneurysmal hemorrhage is pathophysiologically justifiable. Topics: Central Nervous System Diseases; Cerebrospinal Fluid Proteins; Chronic Disease; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Hemorrhage; Humans; Inflammation; Plasminogen | 1977 |
Past and present views of inflammation.
Topics: Blood Coagulation; Complement System Proteins; Fibrin; History, Ancient; History, Medieval; History, Modern 1601-; Inflammation; Kinins; Leukocytes; Mast Cells; Phagocytes; Platelet Aggregation | 1977 |
Experimental allergic encephalomyelitis: role of fibrin deposition in immunopathogenesis of inflammation in rats.
The immunopathogenesis of experimental allergic encephalomyelitis (EAE) is reviewed with special focus on the role of central nervous system fibrin deposition in the inflammatory cascade characterizing this autoimmune disease. Among rats sensitized to whole spinal cord or myelin basic protein of either guinea pig or bovine origin, there is a striking degree of concordance of perivascular fibrin deposits and occurrence of clinical paralytic signs. Neither paralytic signs nor fibrin deposition are temporally related to development of perivascular cellular infiltrates. Rats sensitized to neuroantigen and treated with ancrod, a polypeptide derived from the venom of Agkistrodon rhodostoma, develop profound hypofibrinogenemia, have a marked inhibition of fibrin deposition, and often exhibit no paralytic signs whatsoever. In contrast, cellular infiltrates are not demonstrably influenced by ancrod treatment. Activation of the clotting cascade at loci of developing immune injury of nervous tissue appears to result from and lead to increasing neurovascular permeability and accumulation of edema fluid. Distention of the extracellular space in central and peripheral nervous system tissues by edema fluid appears to be directly responsible for clinical abnormalities characterizing EAE in rats. Cellular infiltrates, on the other hand, appear to be an independent immune response to neuroantigenic sensitization. Topics: Animals; Cattle; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fibrin; Guinea Pigs; Inflammation; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spinal Cord | 1976 |
Inflammatory sequences in acute pulmonary radiation injury.
The histopathologic events in the developing acute pulmonary inflammatory reaction to inhaled particles of Yttrium 90 are detailed. In animals that died or were sacrificed during the first year after inhalation exposure, microscopic findings of acute inflammation predominated and included vascular congestion; stasis, focal hemorrhage; edema; various inflammatory cell infiltrates; cytolysis and desquamation of bronchiolar and alveolar epithelium followed by regeneration; vascular injury and repair; and the eventual development of pulmonary fibrosis. Accumulation of alveolar fibrin deposits was an additional characteristic, though not a constant feature of the early stages of radiation pneumonitis. In addition to the direct effects of radiation on pulmonary cell populations, the histopathologic findings were suggestive of diverse activation of various cellular and humoral mediation systems in their pathogenesis. The potential interrelationships of systems responsible for increased vascular permeability, coagulation and fibrinolysis, chemotaxis, and direct cellular injury were discussed and related to the pathogenesis of the microscopic findings characteristic of early pulmonary radiation injury. Topics: Aerosols; Animals; Capillary Permeability; Environmental Exposure; Fibrin; Inflammation; Lung; Pneumonia; Pulmonary Alveoli; Radiation Injuries, Experimental; Yttrium Radioisotopes | 1976 |
Immunofluorescent investigations in cutaneous vasculitis. II. Histotopical demonstration of IgD and fibrin.
The histotopical distribution of IgD and fibrin was examined in skin lesions of 12 patients with cutaneous vasculitis, by means of the direct IF method. IgD was found in 9 cases mostly in a striking fixation to the PMN-leucocytic inflammation cells. Homogeneous depositions of IgD in cutaneous blood vessel walls were seen twice. In 3 cases with older, lympho-histiocytic infiltrations, IgD was lacking. Fibrin was constantly present in the blood vessel walls of fresh and older vasculitis lesions, and showed up in the regions of "fibrinoid necrosis" in form of distorted vascular rings. Although neither IgD nor fibrin appear in a disease-specific histotopical distribution, their simultaneous in vivo demonstration, connected with the result of vascular bound complement, is a good aid to substantiate the diagnosis of cutaneous vasculitis. Topics: Fibrin; Fluorescent Antibody Technique; Histocytochemistry; Humans; Immunoglobulin D; Inflammation; Microcirculation; Skin; Skin Diseases; Vascular Diseases | 1975 |
Three localized forms of experimental allergic encephalomyelitis: an ultrastructural comparison.
Topics: Animals; Basophils; Brain Edema; Cerebral Cortex; Cyclophosphamide; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Endothelium; Extracellular Space; Fibrin; Freund's Adjuvant; Immunization, Passive; Inflammation; Intercellular Junctions; Lymphocytes; Macrophages; Microscopy, Electron; Myelin Basic Protein; Neutrophils; Pertussis Vaccine; Rats | 1974 |
Pulmonary pathology in stillborn nonhuman primates.
Topics: Animals; Asphyxia Neonatorum; Bacteria; Erythrocytes; Female; Fetal Death; Fibrin; Haplorhini; Humans; Infant, Newborn; Inflammation; Lung; Monkey Diseases; Placenta Diseases; Pregnancy | 1974 |
The chemotactic activity of leucocytes related to blood coagulation and fibrinolysis.
Topics: Animals; Blood Coagulation; Chemotaxis; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Graft Rejection; Humans; Inflammation; Leukocytes; Neutrophils; Rabbits; Species Specificity | 1974 |
Intrauterine pneumonia. An experimental study.
Topics: Amniotic Fluid; Animals; Bronchi; Cesarean Section; Enterococcus faecalis; Escherichia coli; Extraembryonic Membranes; Exudates and Transudates; Female; Fetal Diseases; Fibrin; Gastric Juice; Gestational Age; Inflammation; Injections; Ink; Klebsiella pneumoniae; Leukocytes; Lung; Meconium; Pneumonia; Pregnancy; Pulmonary Alveoli; Rabbits; Staphylococcus | 1973 |
Endothelium and fibrinolysis.
Topics: Adult; Antifibrinolytic Agents; Blood Coagulation; Blood Vessels; Endometrium; Endothelium; Female; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Inflammation; Kidney; Male; Menstruation; Plasminogen; Thrombosis | 1973 |
Intestinal mucosa of dogs with ileocystoplasties. Long-term histologic and histochemical changes.
Topics: Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Atrophy; Dogs; Edema; Electron Transport Complex IV; Epithelium; Female; Fibrin; Histocytochemistry; Ileum; Inflammation; Intestinal Mucosa; L-Lactate Dehydrogenase; Succinate Dehydrogenase; Time Factors; Urinary Bladder; Urinary Diversion | 1973 |
Ultrastructural and associated observations on clinical cases of mastitis in cattle.
Topics: Animals; Basement Membrane; Cattle; Cell Membrane; Cell Nucleus; Collagen; Connective Tissue; Cytoplasm; Cytoplasmic Granules; Endoplasmic Reticulum; Epithelium; Extracellular Space; Female; Fibrin; Glycogen; Inflammation; Leukocytes; Lipids; Mammary Glands, Animal; Mastitis, Bovine; Microscopy, Electron; Milk Proteins; Organoids; Staphylococcal Infections; Streptococcal Infections | 1973 |
BSA-induced allergic arthritis and formol-induced non-allergic arthritis in rabbits. 1. Comparative studies on morphological features and course of the disease.
Topics: Animals; Arthritis; Disease Models, Animal; Female; Fibrin; Formaldehyde; Histiocytes; Inflammation; Injections, Intra-Articular; Knee; Leukocytes; Lymphocytes; Necrosis; Plasma Cells; Rabbits; Serum Albumin, Bovine | 1973 |
Reaction to killed Mycoplasma mycoides in joints in specifically sensitized calves.
Topics: Agar; Animals; Animals, Newborn; Carpal Bones; Cattle; Cattle Diseases; Edema; Fibrin; Histological Techniques; Inflammation; Injections, Intra-Articular; Joints; Mycoplasma; Mycoplasma mycoides; Radius; Synovial Fluid; Synovitis; Tarsal Joints; Time Factors | 1972 |
Acute villous inflammation in the placenta following intrauterine transfusion.
Infection is well recognized as a complication of intrauterine transfusion. The majority of cases are fortunately mild and consist merely of chorio-amnionitis. The present case, of severe type, resulted from contamination of the donor blood with Acinetobacter calcoaceticus. Spread of infection from foetus to mother has been carefully studied and an entirely new type of lesion in the placenta described. This takes the form of acute villous inflammation with resultant micro-abscess formation beneath the trophoblast layer and eventual rupture into the intervillous space. Attempts at localization are poor. Topics: Abscess; Alcaligenes; Bacterial Infections; Blood Transfusion, Intrauterine; Coombs Test; Female; Fetal Diseases; Fibrin; Humans; Inflammation; Male; Myocardium; Placenta Diseases; Pregnancy; Pregnancy Complications; Trophoblasts | 1972 |
Basophilic leukocytes in allergic contact dermatitis.
A variety of cell-mediated hypersensitivity reactions in experimental animals include a prominent infiltrate of basophilic leukocytes. This form of reactivity has been designated cutaneous basophil hypersensitivity and is favored when sensitization to several types of antigen is accomplished without the use of complete Freund's adjuvant. A similar type of hypersensitivity response was sought in man using morphologic techniques which permit identification of basophilic leukocytes. Eight individuals with allergic contact dermatitis to a variety of allergens were studied and six of these developed typical contact reactions with erythema, edema, and epidermal vesicles. The microscopic findings in 3-day biopsies from these individuals differed significantly from classic descriptions of tuberculin hypersensitivity and showed, in addition to mononuclear cells and the characteristic epidermal changes, a substantial infiltrate of basophilic leukocytes and evidence of altered vascular permeability with vascular compaction, dermal edema, and fibrin deposition. Serial biopsies from one individual permitted analysis of the microscopic pathology as it unfolded at successive intervals after patch test. The initial lesion consisted of perivascular accumulations of lymphocytes; this was followed by an influx of basophils and, subsequently, of eosinophils. These findings associate contact allergy in man with the parallel reactions of cutaneous basophil hypersensitivity in animals and provide further evidence for the heterogeneity of the cellular immune response. The data are consistent with the hypothesis that interaction between sensitized lymphocytes and antigen, at a local test site, is responsible for the attraction of basophils. They also directly implicate the clotting system in delayed-type reactions and suggest the possibility of a synergistic relationship between cellular immunity and reactions mediated by basophil-bound, homocytotrophic antibody. Topics: Adult; Alkenes; Basophils; Biopsy; Catechols; Dermatitis, Contact; Edema; Eosinophils; Fibrin; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Inflammation; Lymphocytes; Male; Skin; Skin Tests | 1972 |
[Morphological study of the epithelium during the initial stages of healing of experimental corneal wounds (light and electron microscopy)].
Topics: Animals; Corneal Injuries; Epithelial Cells; Fibrin; Inflammation; Microscopy; Microscopy, Electron; Rats; Time Factors; Wound Healing | 1971 |
Immunofluorescent studies of the skin in cryoglobulinaemic vasculitis.
Topics: Complement System Proteins; Cryoglobulins; Fibrin; Fluorescent Antibody Technique; Humans; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Inflammation; Purpura; Skin; Urticaria; Vascular Diseases | 1971 |
Epithelial-endothelial interaction in the control of inflammation through fibrinolysis.
Topics: Acetylcholine; Biopsy; Bradykinin; Burns; Capillary Permeability; Complement System Proteins; Edema; Epithelium; Fibrin; Fibrinolysis; Fluorescent Antibody Technique; Globulins; Histamine; Histological Techniques; Humans; Hypertrophy; Inflammation; Kallikreins; Leukocytes; Plasminogen; Serotonin; Skin; Time Factors; Urticaria | 1971 |
Staphylococcal clumping and fibrinogen and fibrin degradation products in inflammatory exudate.
Topics: Agglutination; Ascitic Fluid; Fibrin; Fibrinogen; Immunodiffusion; Inflammation; Leukocytes; Staphylococcus; Thrombin | 1971 |
Relationship of experimental allergic encephalomyelitis to human disease.
Topics: Animals; Antigens; Bacterial Infections; Brain; Cross Reactions; Demyelinating Diseases; Disease Models, Animal; Edema; Encephalomyelitis, Autoimmune, Experimental; Exudates and Transudates; Fibrin; Guinea Pigs; Haplorhini; Hemorrhage; Heparin; Humans; Immunization, Passive; Inflammation; Leukocytes; Lymphocytes; Multiple Sclerosis; Myelin Sheath; Pertussis Vaccine; Proteins; Rats; Virus Diseases | 1971 |
[Pathologic-anatomical changes in rheumatoid arthritis and their genesis from the pathologist's viewpoint].
Topics: Arthritis, Rheumatoid; Chronic Disease; Fibrin; Humans; Inflammation; Microscopy, Electron; Necrosis; Synovial Membrane; Synovitis | 1971 |
[Coagulation factors in inflammation].
Topics: Blood Coagulation; Blood Coagulation Factors; Factor XII; Fibrin; Gout; Humans; Inflammation; Phagocytosis; Uric Acid | 1971 |
Fibrinolysis in the control of growth and inflammation in the skin.
Topics: Fibrin; Fibrinolysis; Humans; Inflammation; Skin; Wound Healing | 1971 |
[Effect of an antihistamic preparation (dimedrol) on the morphology and function of connective tissue cellular elements under conditions of aseptic inflammation].
Topics: Animals; Capillary Permeability; Cell Migration Inhibition; Cell Movement; Connective Tissue; Connective Tissue Cells; Depression, Chemical; Diphenhydramine; Disease Models, Animal; Exudates and Transudates; Fibrin; Fibroblasts; Foreign Bodies; Glycoproteins; Glycosaminoglycans; Histocytochemistry; Inflammation; Male; Mast Cells; Methods; Mucoproteins; Neutrophils; Phagocytosis; Proteins; Rats; RNA; Time Factors | 1970 |
[Blood coagulation factors and articular inflammation].
Topics: Arthritis; Blood Coagulation Factors; Calcium; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Factor XI; Factor XII; Factor XIII; Fibrin; Inflammation; Kinins | 1970 |
Ultrastructure of dermal lesions in systemic lupus erythematosus.
Topics: Adult; Autopsy; Biopsy; Connective Tissue; Elastic Tissue; Eosinophils; Female; Fibrin; Histocytochemistry; Humans; Inflammation; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Microscopy; Microscopy, Electron; Middle Aged; Necrosis | 1970 |
How do tissues react to local injury?
Topics: Cell Movement; Edema; Fibrin; Fibrinogen; Inflammation; Leukocytes; Lymphocytes; Macrophages; Microcirculation; Phagocytosis; Wounds and Injuries | 1970 |
[Pathogenesis of arterial occlusive diseases. 3. A model for the study of the pathogenesis of cryoangiitis].
Topics: Animals; Aorta, Abdominal; Blood Platelets; Carotid Arteries; Cold Temperature; Disease Models, Animal; Erythrocytes; Fibrin; Inflammation; Microscopy, Electron, Scanning; Rabbits; Vascular Diseases | 1969 |
[2 different types of pathologic anatomical tissue processes in primary chronic polyarthritis].
Topics: Arteries; Arthritis, Rheumatoid; Chronic Disease; Fibrin; Fibroblasts; Humans; Inflammation; Myocardium; Necrosis; Pericardium; Serous Membrane; Spleen; Tendons | 1969 |
The placenta in premature onset of labour.
Topics: Female; Fibrin; Humans; Infarction; Inflammation; Necrosis; Obstetric Labor, Premature; Placenta; Placentation; Pregnancy | 1969 |
Role of blood coagulation in acute inflammation.
Topics: Acute Disease; Animals; Arthritis; Blood Coagulation; Blood Proteins; Chemotaxis; Dogs; Fibrin; Fibrinogen; Humans; Inflammation; Leukocytes; Skin; Skin Window Technique; Synovial Fluid | 1968 |
The chronicity of inflammation and its significance in rheumatoid arthritis.
Topics: Adjuvants, Immunologic; Animals; Antibodies; Antigens; Arthritis, Rheumatoid; Autoimmune Diseases; Chronic Disease; Fibrin; Gout; Humans; Hypersensitivity, Delayed; Inflammation; Joints; Macrophages; Mycobacterium tuberculosis; Plasma Cells; Polysaccharides; Rabbits; Synovitis; Uric Acid | 1968 |
Human wound repair. II. Inflammatory cells, epithelial-mesenchymal interrelations, and fibrogenesis.
Connective tissue repair was studied in a series of skin wounds in young adult males. The tissues were examined at 3, 12, and 24 hr, and at 2, 3, 5, 7, 14, and 21 days after wounding. The neutrophilic leukocytes contain within membrane-bounded vacuoles some fibrin and serum protein from the wound; however, most of the granulocytes lyse and release their cytoplasmic contents into the extracellular space. The mononuclear cells undergo a series of morphologic alterations during which they develop a modest amount of relatively poorly developed rough endoplasmic reticulum and an extensive system of smooth-surfaced membranes prior to active phagocytosis. They could be clearly distinguished from immature fibroblasts by the differences in the development of their organelles, particularly the rough endoplasmic reticulum. The perivascular connective tissue adjacent to the wound contains cells which appear like poorly developed or immature fibroblasts. The development of these cells into mature fibroblasts can be followed during the different stages of wound repair. Intimate contact was observed between basal cells of the regenerated epidermis and monocytes in the wound below: cytoplasmic projections of the basal cells extended beneath the basement lamina to the surface of the monocytes. Such contacts were seen only on the 4th-7th day after wounding. Their possible significance is discussed. Topics: Blood Proteins; Connective Tissue; Cytoplasm; Endoplasmic Reticulum; Epithelium; Extracellular Space; Fibrin; Fibroblasts; Humans; Inflammation; Male; Membranes; Microscopy, Electron; Monocytes; Neutrophils; Phagocytosis; Skin; Wound Healing | 1968 |
[Enzymatic solubility of fibrin in thrombin and in fibrinous inflammations].
Topics: Blood Platelets; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Inflammation; Microscopy, Phase-Contrast; Peptide Hydrolases; Solubility; Streptokinase; Thrombin; Trypsin | 1966 |
Persistent fibrin.
Topics: Endopeptidases; Fibrin; Fibrinolysis; Humans; Infections; Inflammation; Streptodornase and Streptokinase | 1965 |
THE EFFECT OF CONTINUOUS SUCTION OF THE FRACTURE SITE ON FRACTURE HEALING IN DOGS.
Topics: Animals; Blood Coagulation; Dogs; Drainage; Fibrin; Fracture Healing; Fractures, Bone; Hematoma; Inflammation; Osteotomy; Pathology; Physiology; Research; Suction; Ulna; Wound Healing | 1964 |
[RELATION OF THE DEVELOPMENT OF INFLAMMATION TO THE STATUS OF THE BLOOD COAGULATION SYSTEM].
Topics: Animals; Blood Coagulation; Blood Proteins; Dicumarol; Edema; Epilepsy; Epilepsy, Post-Traumatic; Escherichia coli Infections; Fibrin; Heparin; Inflammation; Leukocytes; Pharmacology; Rabbits; Rats; Research; Skin; Sulfur Isotopes | 1964 |
ULTRASTRUCTURAL STUDY OF FIBRIN DISSOLUTION VIA EMIGRATED POLYMORPHONUCLEAR NEUTROPHILS.
Topics: Cell Physiological Phenomena; Diphtheria Toxoid; Dogs; Electrons; Eosinophils; Exudates and Transudates; Fibrin; Fibrinogen; Fibrinolysis; Fluorescence; Hemostatics; Inflammation; Leukocyte Count; Microscopy; Microscopy, Electron; Microscopy, Fluorescence; Neutrophils; Research; Solubility | 1964 |
SYMPOSIUM ON INFLAMMATION AND ROLE OF FIBRIN IN THE RHEUMATIC DISEASES.
Topics: Fibrin; Humans; Inflammation; Rheumatic Diseases | 1963 |
[ON THE HISTOCHEMISTRY OF FIBRIN].
Topics: Animals; Blood Proteins; Collagen; Connective Tissue; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Glycosaminoglycans; Histocytochemistry; Inflammation; Rabbits; Rats; Research | 1963 |
Studies on the pathogenesis of acute inflammation. II. The relationship of fibrinogen and fibrin to the leucocytic sticking reaction in ear chambers of rabbits injured by heat.
The relation of intravascular fibrin to the leucocytic sticking reaction in ear chambers of rabbits injured by heat was investigated in two ways. First, attempts were made to destroy the thin layer of fibrin believed to coat the surfaces of cells involved in the sticking reaction. Second, white cell sticking was studied after fibrinogen had been removed from the blood stream. The results of these experiments were as follows:- 1. Activation of fibrinolysin in vivo by streptokinase did not impair sticking of white blood cells. 2. Administration of streptokinase parenterally did not lower fibrinogen blood levels appreciably even when the amount used was large. 3. Thromboplastin infusions alone reduced circulating fibrinogen to low levels but leucocytic sticking was not prevented. Furthermore, frequent death of animals due to pulmonary embolism made such experiments prohibitive. 4. Addition of streptokinase to thromboplastin infusions protected against embolic deaths but did not influence sticking even though the fibrinogen levels achieved were quite low. 5. Finally, when thrombin was added to infusions of thromboplastin and streptokinase, no circulating fibrinogen could be detected. Under such circumstances leucocytic sticking following heat injury occurred without reduction. These findings were interpreted as evidence against a primary role of the blood clotting mechanism in causing the sticking of white blood cells to injured endothelium. Alternative explanations were discussed. Topics: Animals; Endothelium; Fibrin; Fibrinogen; Hot Temperature; Inflammation; Leukocyte Count; Leukocytes; Rabbits; Thrombin; Thromboplastin | 1960 |
Effects in patients of intravenous infusions of purified streptokinase preparations.
Topics: Deoxyribonuclease I; Fibrin; Humans; Inflammation; Infusions, Intravenous; Streptodornase and Streptokinase; Streptokinase; Thrombophlebitis | 1957 |
[Fibrinolytic systems and inflammation; fibrinolysis activated by streptofibrinokinases and cytofibrinokinases and large polysulfonate-molecule dyes].
Topics: Coloring Agents; Fibrin; Fibrinolysis; Humans; Inflammation | 1956 |
[Interstitial fibrinous inflammation as an example of dysoria (disordered permeability of the walls of the blood vessels)].
Topics: Blood Vessels; Fibrin; Humans; Inflammation; Permeability | 1950 |
The fibrin barrier regarded as a filter in inflammation.
Topics: Fibrin; Filtration; Humans; Inflammation | 1948 |