fibrin and Fibrosis

Thrombin is a pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis. There is increasing evidence to suggest a role for thrombin in the development of interstitial fibrosis, but interstitial thrombin has not been demonstrated by the direct determination of activity. Rather its presence is inferred by products of thrombin action such as fibrin and activated fibroblasts. This review will focus on possible mechanisms of thrombin formation in the interstitial space, the possible actions of thrombin, processes regulating thrombin activity in the interstitial space, and evidence supporting a role for thrombin in fibrosis.

Topics: Animals; Blood Coagulation; Extracellular Matrix; Extracellular Space; Fibrin; Fibrinogen; Fibroblasts; Fibrosis; Hemostasis; Humans; Liver Cirrhosis; Mice; Platelet Aggregation; Prothrombin; Pulmonary Fibrosis; Signal Transduction; Thrombin

Peyronie's disease is characterized by local fibrosis of the tunica albuginea and relatively rare clinically. Few relevant basic researches could be retrieved, which might be attributed to the absence of a robust animal model of the disease as well as to its rareness. At present, some animal models available for Peyronie's disease have their own merits and demerits. TGF-β1-induced and Fibrin-induced models are lack of penile curvature and calcification/ossification. A surgical model might be established for the acute phase of the disease. The characteristic of a widespread fibrotic process involving many organs in the spontaneous model is quite different from that of human Peyronie's disease. Therefore, choosing the right model is essential for researches. This paper presents an overview of the animal models of Peyronie's disease, meant to provide some reference for the basic research of the disease.

Topics: Animals; Disease Models, Animal; Fibrin; Fibrosis; Humans; Male; Penile Induration; Penis; Transforming Growth Factor beta1

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

Pleural fibrosis can result from a variety of inflammatory processes. The response of the pleural mesothelial cell to injury and the ability to maintain its integrity are crucial in determining whether normal healing or pleural fibrosis occurs. The pleural mesothelial cell, various cytokines, and disordered fibrin turnover are involved in the pathogenesis of pleural fibrosis. The roles of these mediators in producing pleural fibrosis are examined. This article reviews the most common clinical conditions associated with the development of pleural fibrosis. Fibrothorax and trapped lung are two unique and uncommon consequences of pleural fibrosis. The management of pleural fibrosis, including fibrothorax and trapped lung, is discussed.

Topics: Asbestosis; Coronary Artery Bypass; Epithelial Cells; Fibrin; Fibroblast Growth Factor 2; Fibrosis; Hemothorax; Platelet-Derived Growth Factor; Pleura; Pleural Diseases; Pleurisy; Tuberculosis, Pleural

Topics: Fibrin; Fibrosis; Humans; Pleura; Pleural Effusion; Pleurisy

Drawing from diverse sources including epidemiological and clinical data, surgical observations, histopathology, serosal healing responses to fibrin and fibrinolysis, tissue reaction to chronic exposure, and to exo- and endotoxins, new information on mesothelial stem cells, autocrine and paracrine influences on their proliferation and collagen synthesis, and the effect of glucose on fibroconnective tissue, we have begun to piece together the pathogenetic jigsaw of fibrosis in continuous ambulatory peritoneal dialysis (CAPD). The reaction of peritoneal mesothelium and stroma to the stress of continual dialysis results in a spectrum of alterations ranging from opacification through a tanned peritoneum syndrome to sclerosing encapsulating peritonitis (SEP). Any agent that causes irritation of the mesothelial layer and induces serositis, or single severe or multiple episodes of peritonitis resulting in mesothelial loss, predisposes the peritoneum to fibroneogenesis. An accurate definition of the histopathological changes of peritoneal thickening is a prerequisite for defining pathogenesis. This paper is the first attempt to create such a framework. It is evident from many areas of study that fibrin deposition and fibrinolysis, hyalinization of the superficial stromal collagen possibly tanned through nonenzymatic glycosylation by dialysate glucose and the proliferative potential of mesothelial stem cells play an important and possibly interdependent role in excessive fibroneogenesis in certain patients on CAPD. Many of the pieces of the jigsaw are obviously still missing, and the picture is most surely incomplete. Nevertheless, the outline of the pathologic and etiologic landscape should now be discernible.

Topics: Acetates; Adrenergic beta-Antagonists; Anti-Infective Agents, Local; Catheters, Indwelling; Dialysis Solutions; Fibrin; Fibrinolysis; Fibrosis; Humans; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Peritonitis; Sclerosis; Stem Cells

Solid tumors must induce new blood vessels if they are to grow beyond minimal size. As an initial step in this process, tumors secrete a vascular permeability factor that renders the local microvasculature hyperpermeable to fibrinogen and to other plasma proteins. Extravasated fibrinogen is rapidly clotted to crosslinked fibrin gel. Over time, this gel is invaded by macrophages, fibroblasts, and endothelial cells and undergoes "organization," such that it is replaced by vascularized granulation tissue and finally by mature connective tissue. This sequence of events is not unique to tumors but occurs in wound-healing and in a wide variety of other disease processes, including some that prominently affect the lung.

Topics: Animals; Blood Vessels; Capillary Permeability; Fibrin; Fibrosis; Humans; Neoplasms; Neovascularization, Pathologic; Wound Healing

Our current hypothesis is that mechanical damage in the spine such as a disc prolapse can lead directly to pain. However, pain arising for this reason is usually of short duration. In many subjects, however, the mechanical problems lead to vascular damage and, in particular, venous obstruction and dilatation with endothelial damage, fibrin deposition, and intravascular thromboses. In turn, this is associated with perineural and intraneural fibrosis. There is a defect in the fibrinolytic system in the peripheral blood that may be the result of vascular damage but in turn may contribute to the persistence of this problem. Therefore, it seems likely that in many patients with chronic mechanical back pain there are important vascular, fibrotic, and inflammatory components to the problem. Treatment in the future should be directed specifically at these aspects of the disorder and hopefully can lead to better control of symptoms.

Topics: Arachnoiditis; Back Pain; Biomechanical Phenomena; Fibrin; Fibrosis; Humans; Lumbar Vertebrae; Spinal Osteophytosis; Vascular Diseases

Topics: Fibrin; Fibrosis; Humans; Plasma; Thrombosis

Previous studies identified decreased clot permeability, without differences in fibrin fiber density in clots, from patients with cirrhosis compared with those from healthy controls (HCs). Fibrinogen hypersialylation could be the reason for this discrepancy.. The aim of this work was to study mechanical properties of clots and reassess clot permeability in relation to hypersialylation in patients with stable cirrhosis, acute decompensation, and acute-on-chronic liver failure (ACLF). Sepsis patients without liver disease were included to distinguish between liver-specific and inflammation-driven phenotypes.. Pooled plasma was used for rheology and permeability experiments. Permeability was assessed with compression using a rheometer and by liquid permeation. Purified fibrinogen treated with neuraminidase was used to study the effects of fibrinogen hypersialylation on liquid permeation.. Mechanical properties of clots from patients with stable cirrhosis and acute decompensation were similar to those of clots from HCs, but clots from patients with ACLF were softer and ruptured at lower shear stress. Clots from sepsis patients without liver disease were stiffer than those from the other groups, but this effect disappeared after adjusting for increased plasma fibrinogen concentrations. Permeability was similar between clots under compression from HCs and clots under compression from patients but decreased with increasing disease severity in liquid permeation. Removal of fibrinogen sialic acid residues increased permeability more in patients than in controls.. Clots from patients with ACLF have weak mechanical properties despite unaltered fibrin fiber density. Previous liquid permeation experiments may have erroneously concluded that clots from patients with ACLF are prothrombotic as fibrinogen hypersialylation leads to underestimation of clot permeability in this setting, presumably due to enhanced water retention.

Topics: Acute-On-Chronic Liver Failure; Fibrin; Fibrinogen; Fibrinolysis; Fibrosis; Hemostatics; Humans; Liver Cirrhosis; Sepsis; Thrombosis

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

Ionizing radiation, commonly used for head and neck cancer treatment, typically damages the salivary glands, resulting in hyposalivation. The development of treatments to restore this lost function is crucial for improving the quality of life for patients suffering from this condition. To address this clinical need, we have developed an innovative hydrogel by chemically conjugating laminin-1 peptides (A99 and YIGSR) and growth factors, FGF-7 and FGF-10, to fibrin hydrogels. Our results demonstrate that FGF-7/10 and laminin-1 peptides fortified fibrin hydrogel [enhanced laminin-1 peptides fibrin hydrogel (Ep-FH)] promotes salivary gland regeneration and functionality by improving epithelial tissue organization, establishing a healthy network of blood vessels and nerves, while reducing fibrosis in a head and neck irradiated mouse model. These results indicate that fibrin hydrogel-based implantable scaffolds containing pro-regenerative signals promote sustained secretory function of irradiated salivary glands, offering a potential alternative treatment for hyposalivation in head and neck cancer patients undergoing radiation treatment. These unique findings emphasize the potential of fibrin hydrogel-based implantable scaffolds enriched with pro-regenerative signals in sustaining the secretory function of irradiated salivary glands and offer a promising alternative treatment for addressing hyposalivation in head and neck cancer patients undergoing radiation therapy. STATEMENT OF SIGNIFICANCE: Radiation therapies used to treat head and neck cancers often result in damaged salivary gland, leading to severe dryness of the oral cavity. In this study, we engineered FGF-7 and FGF-10 and immobilized them into L

Topics: Animals; Fibrin; Fibrosis; Head and Neck Neoplasms; Humans; Hydrogels; Laminin; Mice; Peptides; Quality of Life; Salivary Glands; Xerostomia

This paper describes a microscale fibroplasia and contraction model that is based on fibrin-embedded lung fibroblasts and provides a convenient visual readout of fibrosis. Cell-laden fibrin microgel drops are formed by aqueous two-phase microprinting. The cells deposit extracellular matrix (ECM) molecules such as collagen while fibrin is gradually degraded. Ultimately, the cells contract the collagen-rich matrix to form a compact cell-ECM spheroid. The size of the spheroid provides the visual readout of the extent of fibroplasia. Stimulation of this wound-healing model with the profibrotic cytokine TGF-β1 leads to an excessive scar formation response that manifests as increased collagen production and larger cell-ECM spheroids. Addition of drugs also shifted the scarring profile: the FDA-approved fibrosis drugs (nintedanib and pirfenidone) and a PAI-1 inhibitor (TM5275) significantly reduced cell-ECM spheroid size. Not only is the assay useful for evaluation of antifibrotic drug effects, it is relatively sensitive; one of the few in vitro fibroplasia assays that can detect pirfenidone effects at submillimolar concentrations. Although this paper focuses on lung fibrosis, the approach opens opportunities for studying a broad range of fibrotic diseases and for evaluating antifibrotic therapeutics.

Topics: Cells, Cultured; Cicatrix; Collagen; Extracellular Matrix; Fibrin; Fibroblasts; Fibrosis; Humans; Transforming Growth Factor beta1

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

This study aimed to analyze the effects of fibrin constructs enhanced with laminin-nidogen, implanted in the wounded rat soft palate. Fibrin constructs with and without laminin-nidogen were implanted in 1 mm excisional wounds in the soft palate of 9-week-old rats and compared with the wounded soft palate without implantation. Collagen deposition and myofiber formation were analyzed at days 3, 7, 28 and 56 after wounding by histochemistry. In addition, immune staining was performed for a-smooth muscle actin (a-SMA), myosin heavy chain (MyHC) and paired homeobox protein 7 (Pax7). At day 56, collagen areas were smaller in both implant groups (31.25 ± 7.73% fibrin only and 21.11 ± 6.06% fibrin with laminin-nidogen)) compared to the empty wounds (38.25 ± 8.89%,

Topics: Actins; Animals; Collagen; Fibrin; Fibrosis; Humans; Laminin; Membrane Glycoproteins; Muscle, Skeletal; Myofibrils; Myosin Heavy Chains; Paired Box Transcription Factors; Palate, Soft; Rats; Regeneration; Wound Healing

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

Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase "acute respiratory distress syndrome" (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.

Topics: Alveolar Epithelial Cells; Autopsy; Betacoronavirus; Coronavirus Infections; Cough; COVID-19; Diabetes Mellitus, Type 2; Fever; Fibrin; Fibrosis; Humans; Hyperplasia; Hypertension; Lung; Lymphocytes; Macrophages; Male; Megakaryocytes; Metaplasia; Middle Aged; Neutrophils; Pandemics; Pneumonia, Viral; Quarantine; SARS-CoV-2; Tachycardia; Thrombosis

Topics: Aged, 80 and over; Aortic Valve; Blood Platelets; Echocardiography, Transesophageal; Fibrin; Fibrosis; Heart Neoplasms; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Male; Myxoma; Neutrophils; Thrombectomy; Thrombosis

 Patients with cirrhosis may acquire profound changes in haemostasis. Although haemostatic changes in cirrhosis have been extensively studied, most studies were performed in groups of patients with mixed aetiology. As thrombotic events appear more common in some aetiologies of disease, notably non-alcoholic steatohepatitis (NASH) and cholestatic disease, we hypothesized that haemostatic changes might be different across aetiologies..  We studied 109 patients with cirrhosis (31 cholestatic liver disease, 23 NASH, 37 alcoholic liver disease [ALD], 18 viral hepatitis) and 44 healthy controls. Patients with malignancy were excluded. Routine diagnostic tests of haemostasis, thrombin generation assays, fibrin permeability assays and a plasma-based fibrinolytic assay were performed..  All patients had comparable severity of disease according to their Model for End-Stage Liver Disease score (9 [7-11]). Plasma levels of von Willebrand factor were substantially elevated across all aetiologies, with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 levels comparable to controls. Thrombin generation capacity was elevated in all aetiologies, most profoundly in ALD. Fibrin permeability was decreased in all aetiologies, which was accompanied by elevated fibrinogen levels. Clot lysis times were prolonged in NASH and cholestatic disease. Plasma levels of individual proteins were similarly altered in all aetiologies..  Our in-depth haemostatic profiling of primary, secondary and tertiary haemostasis in a group of patients with Childs-Turcotte-Pugh A/B cirrhosis showed no large differences between aetiologies, and was consistent with a general hypercoagulable profile in patients with mild cirrhosis. These results suggest that patients with cirrhosis have an increased risk of thrombosis, irrespective of their aetiology.

Topics: Aged; Blood Coagulation; Blood Coagulation Tests; Case-Control Studies; Cholestasis; Female; Fibrin; Fibrinolysis; Fibrosis; Hemostasis; Hemostatics; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases, Alcoholic; Male; Middle Aged; Partial Thromboplastin Time; Thrombin

Esophageal anastomotic leakage (EAL) is a devastating complication for esophagectomy but the available therapies are unsatisfactory. Due to the healing effects of mesenchymal stromal cells (MSCs) and supporting capability of fibrin scaffold (FS), we evaluated the efficacy of a stem-cell therapy for EAL by engrafting adult and autologous MSCs (AAMSCs) in FS and investigated the potential mechanism. Twenty-one rabbits were assigned to AAMSC/FS group (n = 12) and control group (n = 9). After harvested, AAMSCs were identified and then labeled with lenti.GFP. To construct EAL model, a polyethylene tube was indwelled through the anastomosis for 1 week. A total of 2 × 106 AAMSCs in 0.2 ml FS were engrafted onto the EAL for the AAMSC/FS group, whereas FS was injected for control. Magnetic Resonance Imaging (MRI) examination was performed after 5 weeks. Esophageal tissues were harvested for macroscopic, histological analyses, Western blot, and immunohistochemistry at 8 weeks. The animal model of EAL was established successfully. MRI scanning revealed a decreased inflammation reaction in AAMSC/FS group. Accordingly, AAMSC/FS group presented a higher closure rate (83.3% vs. 11.1%, p = .02) and lower infection rate (33.3% vs. 88.9%, p = .02). Histological analyses showed the autografted MSCs resided in the injection site. Furthermore, milder inflammation responses and less collagen deposition were observed in AAMSC/FS group. Western blot and immunohistochemistry studies suggested that the therapeutic effect might be related to the secretions of IL-10 and MMP-9. Engrafting AAMSCs in FS could be a promising therapeutic strategy for the treatment of EAL by suppressing inflammation response and alleviating fibrosis progression. Stem Cells Translational Medicine 2019;8:548-556.

Topics: Anastomotic Leak; Animals; Disease Models, Animal; Esophagectomy; Esophagus; Fibrin; Fibrosis; Interleukin-10; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Rabbits; Tissue Scaffolds; Transplantation, Autologous

The histological findings in the heart in cases of fatal sepsis can show myocytolysis, interstitial fibrosis, necrotic contraction band, mononuclear infiltrates, and interstitial edema, which can be used in post mortem diagnosis of sepsis. Septic myocardial calcification is a very rare condition, and only a few cases have been reported in the literature. In general, the pathogenesis of the myocardial calcification has not been well clarified, but two pathogenic mechanisms have been universally recognized: metastatic or dystrophic. We present a rare case of sepsis-related myocardial calcification. Here we report a case involving a 72-year-old white male who was admitted to a hospital for a polytrauma caused by a motorbike accident. On the 110th day of hospitalization, the patient was diagnosed with a septic process and a subsequent transesophageal echocardiogram revealed the presence of a calcification on the right atrial wall. According to the medical history of the patient there were no systemic factors predisposing to calcium crystals deposition in tissues. Patient died due to multi-organ failure in the course of multimicrobial septic shock during the 149th day. The autopsy revealed both the presence of a greenish-brown formation and a greater consistency of the right atrial wall. The histological investigation of the right atrium wall showed a wide calcification area localized at subendocardial level, which contained fibrin deposition and was surrounded by fibrotic tissue.

Topics: Aged; Calcinosis; Fatal Outcome; Fibrin; Fibrosis; Heart Atria; Humans; Male; Multiple Organ Failure; Sepsis; Shock, Septic

Volumetric muscle defect, caused by trauma or combat injuries, is a major health concern leading to severe morbidity. It is characterized by partial or full thickness loss of muscle and its bio-scaffold, resulting in extensive fibrosis and scar formation. Therefore, the ideal therapeutic option is to use stem cells combined with bio-scaffolds to restore muscle. For this purpose, muscle-derived stem cells (MDSCs) are a great candidate due to their unique multi-lineage differentiation potential. In this study, we evaluated the regeneration potential of MDSCs for muscle loss repair using a novel in situ fibrin gel casting. Muscle defect was created by a partial thickness wedge resection in the tibialis anterior (TA) muscles of NSG mice which created an average of 25% mass loss. If untreated, this defect leads to severe muscle fibrosis. Next, MDSCs were delivered using a novel in situ fibrin gel casting method. Our results demonstrated MDSCs are able to engraft and form new myofibers in the defect when casted along with fibrin gel. LacZ labeled MDSCs were able to differentiate efficiently into new myofibers and significantly increase muscle mass. This was also accompanied by significant reduction of fibrotic tissue in the engrafted muscles. Furthermore, transplanted cells also contributed to new vessel formation and satellite cell seeding. These results confirmed the therapeutic potential of MDSCs and feasibility of direct in situ casting of fibrin/MDSC mixture to repair muscle mass defects.

Topics: Animals; Cell Differentiation; Cells, Cultured; Fibrin; Fibrosis; Mice; Muscle, Skeletal; Regeneration; Stem Cells

We hypothesize that excessive fibrin formation and inflammation induced by antiadhesive material, SurgiWrap (SW), would have an adverse effect on wound healing. It was evaluated by a thyroidectomy murine wound model.. Excessive fibrin formation was induced by isthmectomy without hemostasis. Rats were allocated into isthmectomy with SurgiWrap (I+SW+), I+SW-, I-SW+, I-SW-, and isthmectomy after electrocautery for hemostasis (I+C+SW-). The SWs were placed on the superficial and visceral layers for gross and microscopic evaluation.. Microscopic examination showed collagen deposition occurred in the I-SW- sham group and at a higher level in I+C+SW-. The collagen deposition decreased in groups without SW with time but increased in groups with SW. Use of SW produced more inflammation and more collagen deposition. The I+SW + group developed the largest area of collagen deposition at 4 weeks and more collagen deposition than the I-SW + group.. The SW induced more collagen deposition increasing with time. The collagen deposition produced by SW was worsened by excessive fibrin formation and inflammation.

Topics: Animals; Disease Models, Animal; Female; Fibrin; Fibrosis; Polyesters; Rats; Rats, Sprague-Dawley; Surgical Wound; Thyroidectomy; Wound Healing

Essentials Plg-R. Background Lactational competence requires plasminogen, the zymogen of the serine protease, plasmin. Plg-R

Topics: Animals; Apoptosis; Cell Proliferation; Extracellular Matrix; Female; Fibrin; Fibrinogen; Fibrosis; Genotype; Lactation; Macrophages; Mammary Glands, Animal; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Phenotype; Receptors, Cell Surface

Current cardiac cell therapies cannot effectively target and retain cells in a specific area of the heart. Cell-seeded biological sutures were previously developed to overcome this limitation, demonstrating targeted delivery with > 60% cell retention. In this study, both cell-seeded and non-seeded fibrin-based biological sutures were implanted into normal functioning rat hearts to determine the effects on mechanical function and fibrotic response. Human mesenchymal stem cells (hMSCs) were used based on previous work and established cardioprotective effects. Non-seeded or hMSC-seeded sutures were implanted into healthy athymic rat hearts. Before cell seeding, hMSCs were passively loaded with quantum dot nanoparticles. One week after implantation, regional stroke work index and systolic area of contraction (SAC) were evaluated on the epicardial surface above the suture. Cell delivery and retention were confirmed by quantum dot tracking, and the fibrotic tissue area was evaluated. Non-seeded biological sutures decreased SAC near the suture from 0.20 ± 0.01 measured in sham hearts to 0.08 ± 0.02, whereas hMSC-seeded biological sutures dampened the decrease in SAC (0.15 ± 0.02). Non-seeded sutures also displayed a small amount of fibrosis around the sutures (1.0 ± 0.1 mm

Topics: Animals; Cell Differentiation; Cell Survival; Cell Transplantation; Fibrin; Fibrosis; Heart; Humans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Quantum Dots; Rats; Rats, Nude; Stress, Mechanical; Sutures; Tissue Engineering; Tissue Scaffolds

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

Keloids are wounding-induced tumor-like human scars. Unclear etiology and lack of animal models to reveal disease mechanisms and invent therapies deepen the grievous health and psychosocial state of vulnerable individuals. Epitomizing the injury-repair environment which triggers and fosters keloid formation and essential dermal/epidermal interactions in disease development, the novel animal model was established by implanting porous polyethylene ring-supported plasma/fibrin-based epidermal-dermal skin constructs on the dorsum of athymic NU/J mice. The implants were stable to 18 weeks, contained abundant human cells, and remodeled to yield scar architecture characteristic of keloid fibrosis compared with normal implants and clinical specimens: (1) macroscopic convex or nodular scar morphology; (2) morphogenesis and accumulation of large collagen bundles from collagen-null initial constructs; (3) epidermal hyperplasia, aberrant epidermal-dermal patency, and features of EMT; (4) increased vasculature, macrophage influx, and aggregation; and (5) temporal-spatial increased collagen-inducing PAI-1 and its interactive partner uPAR expression. Development of such pathology in the NU/J host suggests that T-cell participation is less important at this stage than at keloid initiation. These accessible implants also healed secondary excisional wounds, enabling clinically relevant contemporaneous wounding and treatment strategies, and evaluation. The model provides a robust platform for studying keloid formation and testing knowledge-based therapies.

Topics: Animals; Cells, Cultured; Collagen Type I; Dermis; Disease Models, Animal; Epidermal Cells; Fibrin; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Keloid; Mice; Mice, Nude; Plasminogen Activator Inhibitor 1; Transplantation, Heterologous; Wound Healing

Essentials Patients with cirrhosis have hemostatic changes, which may contribute to a risk of thrombosis. This in vitro study compares clot formation and structure between patients and healthy subjects. Clot formation is delayed in patients; ultimately, however, clot permeability is decreased. The thrombogenic structure of fibrin clots may contribute to the thrombotic risk in cirrhosis.. Background and Objectives Patients with cirrhosis can be at risk of thrombotic complications due to an imbalance between hemostatic components. However, little is known on how the disease affects clot generation or how alterations in the structure of fibrin clots may affect the hemostatic function of these patients. Methods We investigated the formation and structure of clots generated with plasma and purified fibrinogen of 42 patients with cirrhosis. Clots generated with plasma and fibrinogen of 29 healthy volunteers were studied for comparison. Clot formation and structure were assessed by turbidity, permeation studies, confocal laser and scanning electron microscopy (SEM). The extent of fibrinogen oxidation was assessed by measuring the carbonyl content of purified fibrinogen samples. Results Tissue factor and thrombin-induced clotting of plasma was delayed in patients. The clotting rate was also decreased, but change in turbidity, fibrin density and fiber thickness were largely comparable to healthy volunteers. Conversely, clot permeability was significantly decreased in patients. When clots were generated with purified fibrinogen, differences in clot formation and structure similar to those in plasma were found. The carbonyl content was increased in patient fibrinogen and correlated with disease severity and clot permeability. Conclusions Delayed clot formation in cirrhosis ultimately results in decreased clot permeability. Similar alterations in clots generated with purified fibrinogen suggest that modifications of the molecule are (partly) responsible. Taken together, these findings are indicative of hypercoagulable features of clots of patients with cirrhosis, which may explain the increased risk of thrombosis associated with this condition.

Topics: Adult; Blood Coagulation; Blood Coagulation Tests; Coagulants; Factor XIII; Female; Fibrin; Fibrinogen; Fibrosis; Healthy Volunteers; Hemostasis; Hemostatics; Humans; Male; Malondialdehyde; Microscopy, Confocal; Microscopy, Electron, Scanning; Middle Aged; Oxygen; Permeability; Thrombosis

Topics: Fibrin; Fibrosis; Humans

Aptamers are oligonucleotides targeting protein-protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low-molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT.. Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti-P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti-P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed.. The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials.

Topics: Animals; Aptamers, Nucleotide; Blood Coagulation; Collagen; Disease Models, Animal; Enoxaparin; Fibrin; Fibrinolytic Agents; Fibrosis; Iliac Vein; Leukocytes; Magnetic Resonance Angiography; P-Selectin; Papio; Phlebography; Platelet Aggregation; Time Factors; Ultrasonography; Venous Thrombosis; Venous Valves; von Willebrand Factor

Treatment of ischemia through therapeutic angiogenesis faces significant challenges. Growth factor (GF)-based therapies can be more effective when concerns such as GF spatiotemporal presentation, bioactivity, bioavailability, and localization are addressed. During angiogenesis, vascular endothelial GF (VEGF) is required early to initiate neovessel formation while platelet-derived GF (PDGF-BB) is needed later to stabilize the neovessels. The spatiotemporal delivery of multiple bioactive GFs involved in angiogenesis, in a close mimic to physiological cues, holds great potential to treat ischemic diseases. To achieve sequential release of VEGF and PDGF, we embed VEGF in fibrin gel and PDGF in a heparin-based coacervate that is distributed in the same fibrin gel. In vitro, we show the benefits of this controlled delivery approach on cell proliferation, chemotaxis, and capillary formation. A rat myocardial infarction (MI) model demonstrated the effectiveness of this delivery system in improving cardiac function, ventricular wall thickness, angiogenesis, cardiac muscle survival, and reducing fibrosis and inflammation in the infarct zone compared to saline, empty vehicle, and free GFs. Collectively, our results show that this delivery approach mitigated the injury caused by MI and may serve as a new therapy to treat ischemic hearts pending further examination.

Topics: Angiogenesis Inducing Agents; Animals; Becaplermin; Cell Proliferation; Cells, Cultured; Chemistry, Pharmaceutical; Chemotaxis; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Drug Combinations; Fibrin; Fibrosis; Gels; Heparin; Human Umbilical Vein Endothelial Cells; Humans; Kinetics; Male; Myocardial Infarction; Myocardium; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Papio; Proto-Oncogene Proteins c-sis; Rats, Sprague-Dawley; Recovery of Function; Solubility; Vascular Endothelial Growth Factor A; Ventricular Function, Left

The Clauss fibrinogen method and thrombin clotting time (TCT) are still routinely used in patients with cirrhosis to define fibrinogen concentration and clotting potential. The thromboelastometric functional fibrinogen FIBTEM assay evaluates the strength of fibrin-based clots in whole blood, providing information on both quantitative deficit and fibrin polymerization disorders.. To compare these three methods of assessing fibrinogen in patients with cirrhosis of different aetiologies, characterized by impairment in fibrinogen concentration as well as functional aberrance.. Sixty patients with alcoholic and 24 patients with cholestatic cirrhosis were included (Child-Pugh score (CPs)A, n=24; B, n=32; C, n=28). All parameters were compared with those from a control group. Maximum clot firmness (MCF) in the FIBTEM test was assessed in regard to its relevance in detection of qualitative fibrinogen disorders in comparison with results obtained by standard measurement methods, i.e. the Clauss fibrinogen method and TCT.. With increased cirrhosis severity, fibrinogen and FIBTEM-MCF levels significantly declined (p=0.002), while TCT was significantly prolonged (p=0.002). In all CPs groups, fibrinogen strongly correlated with FIBTEM-MCF (r=0.77, r=0.72, r=0.74; p<0.001), while cross-correlations of other assays were highly variable. The prevalence of decreased FIBTEM-MCF values (<9 mm) was significantly higher in advanced CPs categories (p=0.027), whereby the highest prevalence was detected in patients with CPsC (10/16; 62.5%). Nine of the 16 patients with decreased FIBTEM-MCF values had also decreased fibrinogen levels, while in the remaining 7 patients fibrinogen levels were within the reference range, indicating the possible presence of qualitatively altered fibrinogen that could be detected by FIBTEM-MCF.. FIBTEM-MCF may be considered as a reliable alternative to standard plasma fibrinogen measurement in cirrhotic patients, especially in evaluating fibrin polymerization disorders in these patients. Further studies are needed to evaluate the usefulness of this assay in predicting bleeding complications in cirrhotic patients as well as monitoring replacement treatment.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Blood Coagulation; Blood Coagulation Tests; Cross-Sectional Studies; Female; Fibrin; Fibrinogen; Fibrosis; Humans; Male; Middle Aged; Reference Values; Thrombelastography; Thrombin; Thrombin Time; Young Adult

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

Topics: Blood Coagulation; Endothelium, Vascular; Endovascular Procedures; Fibrin; Fibrosis; Hot Temperature; Humans; Laser Therapy; Varicose Veins

In fracture treatment, adequate fixation of implants is crucial to long-term clinical performance. Bisphosphonates (BP), potent inhibitors of osteoclastic bone resorption, are known to increase peri-implant bone mass and accelerate primary fixation. However, adverse effects are associated with systemic use of BPs. Thus, Zoledronic acid (ZOL) a potent BP was loaded on bone screws and evaluated in a local delivery model. Whilst mid- to long-term effects are already reported, early cellular events occurring at the implant/bone interface are not well described. The present study investigated early tissue responses to ZOL locally delivered, by bone screw, into a compromised cancellous bone site.. ZOL was immobilized on fibrinogen coated titanium screws. Using a bilateral approach, ZOL loaded test and non-loaded control screws were implanted into femoral condyle bone defects, created by an overdrilling technique. Histological analyses of the local tissue effects such as new bone formation and osteointegration were performed at days 1, 5 and 10.. Histological evaluation of the five day ZOL group, demonstrated a higher osseous differentiation trend. At ten days an early influx of mesenchymal and osteoprogenitor cells was seen and a higher level of cellular proliferation and differentiation (p < 5%). In the ZOL group bone-to-screw contact and bone volume values within the defect tended to increase. Local drug release did not induce any adverse cellular effects.. This study indicates that local ZOL delivery into a compromised cancellous bone site actively supports peri-implant osteogenesis, positively affecting mesenchymal cells, at earlier time points than previously reported in the literature.

Topics: Animals; Bone Resorption; Bone Screws; Coated Materials, Biocompatible; Diphosphonates; Drug Evaluation, Preclinical; Exudates and Transudates; Femur; Fibrin; Fibrinogen; Fibrosis; Imidazoles; Implants, Experimental; Macrophages; Male; Mesoderm; Osseointegration; Osteoclasts; Pilot Projects; Rabbits; Titanium; Zoledronic Acid

To find out if adipose-derived stem cells (ASC) and platelet-rich fibrin (PRF), alone or combined, had any effect on the repair of maxillofacial soft tissue defects in irradiated minipigs, ASC were isolated, characterised, and expanded. Twenty female minipigs, the right parotid glands of which had been irradiated, were randomly divided into 4 groups of 5 each: those in the first group were injected with both ASC and PRF (combined group), the second group was injected with ASC alone (ASC group), the third group with PRF alone (PRF group), and the fourth group with phosphate buffer saline (PBS) (control group). Six months after the last injection, the size and depth of each defect were assessed, and subcutaneous tissues were harvested, stained with haematoxylin and eosin, and examined immunohistologically and for apoptosis. Expanded cells were successfully isolated and identified. Six months after injection the defects in the 3 treated groups were significantly smaller (p<0.001) and shallower (p<0.001) than those in the control group. Those in the combined group were the smallest and shallowest. Haematoxylin and eosin showed that the 3 treated groups contained more subcutaneous adipose tissue than the control group, and also had significantly greater vascular density (p<0.001) and fewer apoptotic cells (p<0.001). Both ASC and PRF facilitate the repair of defects in maxillofacial soft tissue in irradiated minipigs, and their combined use is more effective than their use as single agents.

Topics: Adipose Tissue; Animals; Apoptosis; Blood Platelets; Collagen; Elastic Tissue; Female; Fibrin; Fibrosis; Immunohistochemistry; Lymphocytes; Macrophages; Neovascularization, Physiologic; Parotid Gland; Radiation Dosage; Radiation Injuries, Experimental; Random Allocation; Stem Cell Transplantation; Subcutaneous Tissue; Swine; Swine, Miniature; Time Factors; Wound Healing

Cell-based angiogenic therapy for ischemic heart failure has had limited clinical impact, likely related to low cell retention (<1%) and dispersion. We developed a novel, tissue-engineered, hydrogel-based cell-delivery strategy to overcome these limitations and provide prolonged regional retention of myocardial endothelial progenitor cells at high cell dosage.. Endothelial progenitor cells were isolated from Wistar rats and encapsulated in fibrin gels. In vitro viability was quantified using a fluorescent live-dead stain of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells. Endothelial progenitor cell-laden constructs were implanted onto ischemic rat myocardium in a model of acute myocardial infarction (left anterior descending ligation) for 4 weeks. Intramyocardial cell injection (2 × 10(6) endothelial progenitor cells), empty fibrin, and isolated left anterior descending ligation groups served as controls. Hemodynamics were quantified using echocardiography, Doppler flow analysis, and intraventricular pressure-volume analysis. Vasculogenesis and ventricular geometry were quantified. Endothelial progenitor cell migration was analyzed by using endothelial progenitor cells from transgenic enhanced green fluorescent protein(+) rodents.. Endothelial progenitor cells demonstrated an overall 88.7% viability for all matrix and cell conditions investigated after 48 hours. Histologic assessment of 1-week implants demonstrated significant migration of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells from the fibrin matrix to the infarcted myocardium compared with intramyocardial cell injection (28 ± 12.3 cells/high power field vs 2.4 ± 2.1 cells/high power field, P = .0001). We also observed a marked increase in vasculogenesis at the implant site. Significant improvements in ventricular hemodynamics and geometry were present after endothelial progenitor cell-hydrogel therapy compared with control.. We present a tissue-engineered, hydrogel-based endothelial progenitor cell-mediated therapy to enhance cell delivery, cell retention, vasculogenesis, and preservation of myocardial structure and function.

Topics: Animals; Cell Culture Techniques; Cell Movement; Cell Survival; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Fibrin; Fibrosis; Green Fluorescent Proteins; Hemodynamics; Hydrogels; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Wistar; Stem Cell Transplantation; Time Factors; Tissue Engineering; Tissue Scaffolds; Transfection; Ventricular Function, Left; Ventricular Pressure

The purpose of this study was to evaluate the biocompatibility of a self-adhesive gutta-percha material and compare it with that of conventional gutta-percha.. Standard quantities of bioactive gutta-percha and conventional gutta-percha were directly inserted subcutaneously into the dorsal connective tissue of 30 BALB/c mice according to ISO 10993-6. After 7, 21, and 63 days each, 10 animals were euthanized, and the materials and surrounding tissue were removed. Tissue samples were subjected to histological processing resulting in 5-μm-thick slices stained with hematoxylin-eosin and Gomori trichrome stain. A grade ranging from I-IV was used to classify the inflammatory reaction. The Mann-Whitney U test with Bonferroni correction was used to compare the grade of inflammation induced by the materials at each time point. Qualitative evaluation of biocompatibility over time was also performed.. Bioactive gutta-percha was more biocompatible than conventional gutta-percha at each time interval (P < .05). Tissue exposed to bioactive gutta-percha reached "no inflammation" (grade I) at the 21-day interval, whereas it took 63 days for the conventional gutta-percha to reach the "slight inflammation" level (grade II).. Bioactive gutta-percha presented good tissue reaction at all time points. It may serve as an alternative to gutta-percha in terms of biocompatibility.

Topics: Animals; Biocompatible Materials; Cellulitis; Collagen; Edema; Fibrin; Fibroblasts; Fibrosis; Gutta-Percha; Hemiterpenes; Latex; Macrophages; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Neutrophils; Subcutaneous Tissue; Time Factors; Zinc Oxide

Recently, efforts to control the propagation of the fibrin gel matrix (FGM) are under investigation as a means of limiting the formation of post-surgical adhesions (PSAs). A series of polymeric biomaterials based on block co-polymers of methacrylic acid (MA) and methoxypolyethylene glycol methacrylate (PEGMA) have been synthesized and characterized in order to study the impact of molecular architecture on the performance of these materials in suppressing FGM development. A robust synthetic strategy has been developed to facilitate the well controlled variation of numerous structural properties, including the relative size of each polymer block, the total polymer length, and the length of poly(ethylene glycol) (PEG) chain length, and to incorporate the fibrin-targeting pentapeptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA). Preliminary investigations, based on quartz crystal microgravimetry (QCM), indicate the importance of molecular architecture in modulating the FGM propagation from model surfaces.

Topics: Chromatography, High Pressure Liquid; Fibrin; Fibrosis; Gels; Hydrolysis; Molecular Structure; Oligopeptides; Polymers; Postoperative Complications; Proton Magnetic Resonance Spectroscopy; Quartz Crystal Microbalance Techniques

Proteins are major plaque components, and their degradation is related to the plaque instability. We sought to assess the feasibility of magnetization transfer (MT) magnetic resonance (MR) for identifying fibrin and collagen in carotid atherosclerotic plaques ex vivo.. Human carotid artery specimens (n = 34) were obtained after resection from patients undergoing endarterectomy. MR was completed within 12 hr after surgery on an 11.7T MR microscope prior to fixation. Two sets of T1W spoiled gradient echo images were acquired with and without the application of a saturation pulse set to 10 kHz off resonance. The magnetization transfer ratio (MTR) was calculated, and the degree of MT contrast was correlated with histology.. MT with appropriate calibration clearly detected regions with high protein density, which showed a higher MTR (thick fibers (collagen type I) (54 ± 8%)) compared to regions with a low amount of protein including lipid (46 ± 8%) (p = 0.05), thin fibers (collagen type III) (11 ± 6%) (p = 0.03), and calcification (6.8 ± 4%) (p = 0.02). Intraplaque hemorrhage (IPH) with different protein density demonstrated different MT effects. Old (rich in protein debris) and recent IPH (rich in fibrin) had a much higher MTR 69 ± 6% and 55 ± 9%, respectively, compared to fresh IPH (rich in intact red blood cells)(9 ± 3%).. MT MR enhances plaque tissue contrast and identifies the protein-rich regions of carotid artery specimens. The additional information from MTR of IPH may provide important insight into the role of IPH on plaque stability, evolution, and the risk for future ischemic events.

Topics: Aged; Analysis of Variance; Biomarkers; Boston; Carotid Arteries; Carotid Artery Diseases; Collagen; Endarterectomy, Carotid; Feasibility Studies; Female; Fibrin; Fibrosis; Humans; Lipids; Magnetic Resonance Imaging; Male; Middle Aged; Predictive Value of Tests

A girl aged 21 months and a boy aged 3 years both died of hemorrhage from intestinal and mesenteric lacerations due to inflicted blunt abdominal trauma. Histologic examination of sections from the areas of duodenal and mesenteric lacerations confirmed changes of acute injury with hemorrhage, acute inflammatory infiltrates, and surface fibrin deposition. In addition, in both cases, there was also evidence of much longer-standing trauma with mesenteric fibrosis and hemosiderin-containing macrophages (the latter in keeping with previous hemorrhage). In the absence of a history of surgery and local inflammatory disease, these findings suggest that these children had suffered previous abdominal trauma, possibly from similar types of injuries. Scarring of the mesentery and intestine in cases of lethal childhood blunt abdominal trauma may provide evidence of previous similar, significant although sublethal tissue damage. Extensive histologic sampling of abdominal organs and tissues including the mesentery can, therefore, be extremely useful in such cases.

Topics: Cell Proliferation; Child, Preschool; Contusions; Female; Fibrin; Fibroblasts; Fibrosis; Forensic Pathology; Hemorrhage; Hemosiderin; Humans; Infant; Intestines; Macrophages; Male; Mesentery; Neutrophils; Pancreas; Recurrence; Wounds, Nonpenetrating

Although both sirolimus (CYPHER) and paclitaxel (TAXUS) drug-eluting stents have demonstrated efficacy and safety in clinical trials, human autopsy data have raised concerns about long-term healing and the potential for local inflammatory reactions.. Overlapping stents (CYPHER drug-eluting stents, Bx SONIC bare metal stents, TAXUS drug-eluting stents, and Liberté bare metal stents) were implanted in noninjured coronary arteries of 58 domestic swine. Histopathological evaluation of proximal, overlapped, and distal stented segments was determined with emphasis on inflammation at 30, 90, and 180 days. Circumferential granulomatous inflammation in all stented segments was defined as inflammation consisting of macrophages, multinucleated giant cells, lymphocytes, and granulocytes, including many eosinophils, adjacent to almost all struts. Circumferential granulomatous inflammation was more prevalent in CYPHER (9 of 23, 39%) compared with TAXUS (1 of 21, 5%; P=0.01) and control bare metal stents (0 of 44) in the combined 90- and 180-day cohorts. Only CYPHER specimens showed marked adventitial inflammation (P=0.0025) and fibrosis (P=0.0055) accompanied by extensive remodeling. Fibrin deposition within neointima and medial smooth muscle cell death were greater (both P<0.001) in TAXUS than CYPHER at 30 days, with more fibrin in TAXUS than CYPHER through 90 days (P<0.05).. Although these data cannot be directly extrapolated to humans, the high prevalence in this porcine model of diffuse granulomatous inflammation seen with CYPHER stents, persisting at 180 days and associated with extensive remodeling of the artery, and persistent para-strut fibrin deposition with TAXUS stents emphasize the need for further investigation of biocompatibility with these and other novel combination drug/polymer drug-eluting stents.

Topics: Animals; Arteritis; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Eosinophils; Female; Fibrin; Fibrosis; Granuloma, Foreign-Body; Paclitaxel; Sirolimus; Swine; Tunica Intima

In this study, temporal and spatial distribution of three TGF-beta isoforms and their downstream signaling pathways including pSmad2 and p38MAPK were examined during fibrotic wound repair. In normal chick corneas, TGF-beta1, -2, and -3 were weakly detected in Bowman's layer (BL). In healing corneas, TGF-beta1 was primarily deposited in the fibrin clot and the unwounded BL. TGF-beta2 was highly expressed in healing epithelial and endothelial cells, and numerous active fibroblasts/myofibroblasts. TGF-beta3 was mainly detected in the unwound region of basal epithelial cells. alpha-Smooth muscle actin (alpha-SMA) was initially appeared in the posterior region of repairing stroma at day 3, and was detected in the entire healing stroma by day 7. Notably, alpha-SMA was absent in the central region of healing stroma by day 14, and its staining pattern was similar to those of TGF-beta2 and p38MAPK. By contrast, pSmad2 was mainly detected in the fibroblasts. In normal cornea, laminin was mainly detected in both epithelial basement membrane (BM) and Descemet's membrane (DM). By contrast to reconstitution of the BM in the wound region, the DM was not repaired although endothelial layer was regenerated, indicating that high levels of TGF-beta2 were released into the posterior region of healing stroma on day 14. High levels of alpha-SMA staining, shown in cultured repair stromal cells from healing corneas on day 14 and in TGF-beta2 treated normal stromal cells, were significantly reduced by p38MAPK inhibition. Collectively, this study suggests that TGF-beta2-mediated myofibroblast transformation is mediated, at least partly, by the p38MAPK pathway in vivo.

Topics: Ablation Techniques; Actins; Aging; Animals; Basement Membrane; Bowman Membrane; Cells, Cultured; Chickens; Cornea; Corneal Injuries; Descemet Membrane; Fibrin; Fibrosis; Intracellular Signaling Peptides and Proteins; Laminin; p38 Mitogen-Activated Protein Kinases; Protein Isoforms; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Smad2 Protein; Stromal Cells; Time Factors; Transforming Growth Factor beta; Wound Healing

Topics: Animals; Blood Coagulation; Disease Models, Animal; Factor V; Fibrin; Fibrosis; Humans; Liver Cirrhosis, Experimental; Mice; Models, Biological

The activity of plasmin plays a critical role in the development of chronic glomerulonephritis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of plasmin generation. We hypothesized that TAFI is involved in the pathogenesis of glomerulonephritis because it inhibits plasmin generation. To demonstrate this hypothesis, we compared the development of immune complex-mediated glomerulonephritis in wild-type and TAFI-deficient mice. After six weeks of treatment with horse spleen apoferritin and lipoplysaccharide to induce glomerulonephritis, mice deficient in TAFI had significantly better renal function as shown by lower concentrations of albumin in urine and blood urea nitrogen compared to wild-type mice. In addition, the activity of plasmin and matrix metalloproteinases was significantly increased, and mesangial matrix expansion and the deposition of collagen and fibrin in kidney tissues were significantly decreased in TAFI-knockout mice as compared to their wild-type counterparts. Depletion of fibrinogen by batroxobin (Defibrase) treatment led to equalization of the renal function and the amount of collagen deposition in the kidneys of TAFI-knockout and wild-type mice with immune complex-mediated glomerulonephritis. Together these observations suggest that TAFI-mediated inhibition of plasmin generation plays a role in the pathogenesis of glomerulonephritis, and that it may constitute a novel molecular target for the therapy of this disease.

Topics: Animals; Antigen-Antibody Complex; Batroxobin; Carboxypeptidase B2; Complement C3; Cytokines; Disease Models, Animal; Disease Progression; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Fibrosis; Glomerulonephritis; Kidney; Kidney Function Tests; Matrix Metalloproteinases; Mice; Mice, Knockout; Time Factors

Reports analyzing the histopathological differences between encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis (non-EPS) and those comparing the pathology of early and late EPS are limited. We present pathological comparisons between EPS and non-EPS, also between the early and late EPS stages. We compared peritoneal membrane (PM) samples (Group B) of 12 EPS patients (Group A) and 23 non-EPS cases regarding; mesothelial loss, submesothelial compact zone degenerated layer and compact zone thicknesses, densities of total and diseased vessels, fibrin stain, new membrane formation and degenerative changes. Group A was subdivided into 7 early (group A1) and 8 late (group A2) EPS cases; we compared both subgroups in the same manner and finally compared groups A1, A2, and B. No differences were found between groups A and B in the incidences of mesothelial detachment, new membrane formation and compact zone degenerative changes between the two groups. Furthermore, there were no differences in compact zone thickness, and vascular densities in the compact zone of respective vascular grade. Whereas, fibrin deposition and thickness of the submesothelial degenerated layer were significantly higher in group A than group B (P = 0.01 and 0.05, respectively), and the thickness of the compact zone was less in group A1 than in group A2 (P = 0.03). Positive fibrin stains and thick degenerative compact zone layers are important pathological findings in EPS. Angiogenesis, vasculopathy, new membrane formation, fibrosis and degenerative changes of the compact zone are not unique characteristics for EPS. Larger size studies are recommended to verify this issue.

Topics: Adult; Aged; Biopsy; Epithelium; Female; Fibrin; Fibrosis; Humans; Male; Middle Aged; Neovascularization, Pathologic; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Sclerosis; Time Factors

Bone marrow-derived mononuclear cell (BMNC) transplantation provides the possibility of rescue or regeneration of myocardium lost during acute myocardial infarction (AMI). The extensive death of transplanted cells and the lack of sustained engraftment may limit its application. We investigated whether delivery of BMNCs by an injectable PEGylated fibrin biomatrix that covalently binds hepatocyte growth factor (HGF) would enhance the rate of cell engraftment and improve cardiac function. Balb/C female mice with AMI secondary to left anterior descending coronary ligation were randomly assigned to one of six groups: the Saline control group (n = 8) received a myocardial injection of saline (50 microL); the Cell group (n = 10) received a myocardial injection in the peri-infarct and infarct zones consisting of 500,000 murine BMNCs suspended in 50 microL saline; and the Biomatrix + HGF (n = 9) and Biomatrix + HGF + Cell (n = 9) group hearts received the HGF-loaded injectable biomatrix (identical volume) with or without entrapped BMNCs. Control groups consisting of the biomatrix alone (n = 9) and Biomatrix + Cells (n = 9) without HGF were also included for comparison. The left ventricular (LV) function was measured by echocardiography at days 14 and 28 post-MI. All animals were euthanized 4 weeks after AMI and transplantation for evaluation of angiogenesis, apoptosis, and fibrosis by immunohistochemistry. Cell prevalence rate at 4 weeks increased 15-fold in hearts receiving the Biomatrix + HGF + Cell delivery (p < 0.01), which was accompanied by the lowest levels of apoptosis and the highest LV function recovery among the treated groups.

Topics: Animals; Apoptosis; Cell Lineage; Echocardiography; Female; Fibrin; Fibrosis; Hepatocyte Growth Factor; In Situ Nick-End Labeling; Laminin; Mice; Mice, Inbred BALB C; Myocardial Contraction; Myocardium; Neovascularization, Pathologic; Polyethylene Glycols; Stem Cell Transplantation; Ventricular Function, Left

Interstitial fibrosis is a universal feature of progressive kidney disease. Urokinase-type plasminogen activator (uPA) is thought to participate for several reasons: 1) uPA is produced predominantly in kidney, 2) its inhibitor plasminogen activator inhibitor-1 (PAI-1) is a strong promoter of interstitial fibrosis, whereas its receptor (uPAR) attenuates renal fibrosis, 3) uPA reduces fibrosis in liver and lung, and 4) uPA can activate hepatocyte growth factor (HGF), a potent antifibrotic growth factor. The present study tested the hypothesis that endogenous uPA reduces fibrosis severity by investigating the unilateral ureteral obstruction (UUO) model in wild-type (WT) and uPA-/- mice. Several outcomes were measured: renal collagen 3-21 days after UUO, macrophage accumulation (F4/80 Western blotting), interstitial myofibroblast density (alpha-smooth muscle actin immunostaining), and tubular injury (E-cadherin and Ksp-cadherin Western blotting). None of these measures differed significantly between WT and uPA-/- mice. uPA genetic deficiency was not associated with compensatory changes in renal uPAR mRNA levels, PAI-1 protein levels, or tissue plasminogen activator activity levels after UUO. Despite the known ability of uPA to activate latent HGF, immunoblotting failed to detect significant differences in levels of the active HGF alpha-chain and phosphorylated cMET (the activated HGF receptor) between the WT and uPA-/- groups. These findings suggest that the profibrotic actions of PAI-1 are uPA independent and that an alternative pathway must activate HGF in kidney. Finally, these results highlight a significant organ-specific difference in basic fibrogenic pathways, as enhanced uPA activity has been reported to attenuate pulmonary and hepatic fibrosis.

Topics: Animals; Blotting, Western; Collagen; Disease Progression; Fibrin; Fibroblasts; Fibrosis; Genotype; Hepatocyte Growth Factor; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Hydrolases; Phenotype; Phosphorylation; Plasminogen Activators; RNA, Messenger; Ureteral Obstruction; Urokinase-Type Plasminogen Activator

Topics: Aged; Bursitis; Female; Femur; Fibrin; Fibrosis; Humans; Image Enhancement; Ultrasonography

To evaluate the utility of peritoneal pathologic samples, unrelated to peritoneal dialysis (PD) treatment, for the study of peritoneal fibrosis and inflammation.. Comparative morphologic and immunohistochemical study of peritoneal pathologic samples unrelated to PD with peritoneal biopsies from PD patients with special emphasis on the expression of myofibroblastic and epithelial-to-mesenchymal transition markers.. Regarding morphology, PD-related simple fibrosis was less cellular, with greater stromal hyalinization, determining a homogeneous, hypocellular aspect of the submesothelium. In contrast, non-PD fibrosis was more cellular with an extracellular matrix showing a dense and fibrillar quality with wide bundles of collagen. Hylinazing vasculopathy was only present in PD samples. Myofibroblastic differentiation and epithelial-to-mesenchymal transition were common findings in all situations of peritoneal fibrosis. Calponin and calretinin are useful cellular markers to study such fibrogenic mechanisms and correlate with other well-known markers such as a -SMA and cytokeratins. Their expression was much more intense in those samples showing acute inflammation (peritonitis).. Non-PD models of peritoneal fibrosis seem very useful to evaluate important features of human peritoneal pathology such us fibrogenesis, and inflammation. Fibrogenic events such as myofibroblastic differentiation and epithelial-to-mesenchymal transition are evident in these tissue samples allowing us to use them as an accessible source for in vivo and ex vivo studies. Both events show their maximal expression in situations of acute inflammation supporting the important role that peritonitis episodes play in the progression of fibrosis.

Topics: Actins; Biomarkers; Biopsy; Calbindin 2; Calcium-Binding Proteins; Calponins; Case-Control Studies; Cell Differentiation; Edema; Epithelium; Fibrin; Fibroblasts; Fibrosis; Hernia, Inguinal; Humans; Hyalin; Keratins; Microfilament Proteins; Neutrophils; Peritoneum; S100 Calcium Binding Protein G; Sclerosis; Tissue Adhesions

The deposition of fibrin is an integral part of the tissue repair process, but its persistence is also associated with a number of fibrotic conditions. This study addressed the hypothesis that reduced fibrinolysis and fibrin persistence are associated with an enhanced accumulation of collagen and the development of skin fibrosis. Decreased fibrinolysis was confirmed in fibrin gel cultures that contained human dermal fibroblasts plus the specific plasmin inhibitor alpha(2)-antiplasmin or dermal fibroblasts isolated from plasminogen activator (PA)-deficient mice. Collagen accumulation was significantly increased in the presence of inhibitor and in tPA-deficient, but not uPA-deficient, fibroblasts compared with controls. These findings were also confirmed using a skin fibrosis model in which multiple injections of fibrin were given subcutaneously to PA-deficient mice. Injection sites from tPA-deficient mice displayed significantly increased collagen levels compared with uPA-deficient mice and wild-type controls. Up-regulation of fibroblast procollagen gene expression and reduced activation of pro-MMP-1 appeared to mediate the increase in collagen by human dermal fibroblasts in the presence of alpha2-antiplasmin. These findings suggest that persistent fibrin is associated with enhanced collagen accumulation that may result in the development of fibrotic skin disorders in which reduced fibrinolysis is a feature.

Topics: Animals; Cells, Cultured; Collagen; Collagenases; Enzyme Activation; Enzyme Precursors; Fibrin; Fibrinolysin; Fibrinolysis; Fibroblasts; Fibrosis; Gels; Gene Expression; Humans; Injections, Subcutaneous; Male; Matrix Metalloproteinase 1; Mice; Procollagen; Skin; Tissue Plasminogen Activator

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

Elevated circulatory levels of many blood coagulation factors are known to be a risk factor for deep vein thrombosis in humans. Here we report the first direct demonstration of a close association between elevated circulatory factor IX levels in mice with thrombosis as well as myocardial fibrosis. Transgenic mice overexpressing human factor IX at persistently high levels died at much younger ages than their cohorts expressing lower levels, or nontransgenic control animals. The median survival age of animals was inversely related to the circulatory levels of human factor IX. Prematurely dying animals had focal fibrotic lesions predominantly present in the left ventricular myocardium, and vasculatures in these lesions showed fibrin deposition. Thromboemboli were also present in other organs, including lung and brain. These observations support the hypothesis that persistently high circulatory levels of factor IX are a risk factor not only for thrombosis and/or thromboembolism, but also for myocardial fibrosis mimicking human myocardial infarction.

Topics: Animals; Coronary Thrombosis; Disease Models, Animal; Factor IX; Female; Fibrin; Fibrosis; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Recombinant Fusion Proteins; Risk Factors; Thromboembolism; Thrombophilia

To investigate the role of fibrin in inducing fibrosis in the tunica albuginea (TA) of the rat penis, to develop a new animal model for Peyronie's disease (PD).. The TA of rats (five per group per period) were injected with either saline, fibrin, transforming growth factor-beta1 (TGF-beta1) or TGF-beta1 plus fibrin; the rats were killed at 1, 3, and 6 weeks after injection. Images were analysed quantitatively from tissue sections stained for collagen (Masson trichrome), fibrin (Verhoeff's stain) and elastin (Hart's stain), and immunostained for TGF-beta1, inducible nitric oxide synthase (iNOS), heme oxygenase 1 (HO1), alpha-smooth muscle actin (ASMA), apoptosis (TUNEL) and plasminogen activator inhibitor (PAI). Collagen fibre organization was characterized by electron microscopy. Human PD plaque tissue and normal human TA were assayed for fibrin by immunohistochemistry in nine samples.. At 1 week after injection of fibrin into the rat TA, only oedema was present; at 3 weeks, the oedema developed into a characteristic fibrotic PD-like plaque. The injection of TGF-beta1 into the TA also induced oedema in the TA at 1 and 3 weeks but there was very little evidence of a recognisable plaque at either time. Injection with TGF-beta1 plus fibrin resulted in oedema at 1 week but at 3 weeks there was a smaller plaque than with fibrin only. At 6 weeks the induced plaques in the fibrin-only and fibrin + TGF-beta1 groups persisted, and were comparable with those elicited at this time by TGF-beta1 alone. The control animals showed no pathology at any of the sample times. At 3 weeks the PD plaque induced by injection with fibrin alone had not only greater expression of TGF-beta1 than the TA of the animals receiving TGF-beta1 alone, but also greater levels of other markers of fibrosis, e.g. HO1 (reactive oxygen species), ASMA (presence of myofibroblasts), apoptosis, and PAI (inhibitor of fibrinolysis). iNOS, a known antifibrotic agent, was also increased. In human PD plaque tissue, fibrin was detected by immunohistochemistry in all nine specimens.. These results suggest that fibrin, when introduced into the TA of the rat penis, acts as a potential profibrotic protein, possibly via the local release of TGF-beta1, and induces a plaque not only histologically similar to that induced by TGF-beta1 but to that of the human condition. Because fibrin can extravasate from the blood into the human TA after an injury to the TA, and because fibrin persists in the plaque tissue, we hypothesise that fibrin may play a key role in the pathogenesis of human PD.

Topics: Animals; Disease Models, Animal; Fibrin; Fibrosis; Humans; Immunohistochemistry; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Penile Induration; Penis; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

Topics: Anterior Chamber; Cataract Extraction; Child; Child, Preschool; Fibrin; Fibrinolytic Agents; Fibrosis; Heparin, Low-Molecular-Weight; Humans; Lens Capsule, Crystalline; Postoperative Complications; Risk Factors; Vitrectomy

Mice with homozygous deletion of the plasminogen activator inhibitor-1 gene (PAI-1(-/-)) are relatively protected from bleomycin-induced pulmonary fibrosis. At least part of the protective effect appears to occur during the latter stages of the pathological process when fibrotic tissue is being deposited. To investigate the effect of PAI-1 deficiency on fibrosis, we studied the accumulation of fibrotic tissue within subcutaneously implanted polyvinyl alcohol sponges. Similar to the effect of PAI-1 deficiency on bleomycin-induced pulmonary fibrosis, the accumulation of fibrotic tissue within implanted sponges occurred more slowly in PAI-1(-/-) compared to wild-type mice. Another striking difference observed in the PAI-1(-/-) mice was the rapid removal of a fibrin-rich matrix that formed within the sponges by 1 day after implantation in both wild-type and PAI-1(-/-) mice. The pattern of connective tissue invasion also differed: cells in wild-type mice infiltrated as individually penetrating cells whereas in PAI-1(-/-) mice they did so as a well-demarcated advancing front. Providing an alternative provisional matrix by impregnating sponges with a low concentration of collagen before implantation corrected the changes induced by PAI-1 deficiency. In conclusion, PAI-1 deficiency appears to affect fibrotic tissue formation in part by altering the provisional matrix that forms soon after tissue injury.

Topics: Animals; Collagen; Extracellular Matrix; Fibrin; Fibrosis; Foreign Bodies; Hydroxyproline; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; Polyvinyl Alcohol; Prostheses and Implants

Coronary remodeling based on collagen abnormalities in diabetes might be associated with potential interactions between the matrix metalloproteinase (MMP) system, which regulates extracellular matrix turnover, and the fibrinolytic system, which is involved in the fibrin degradation process. We characterized the profiles of the MMP and fibrinolytic systems in insulin-resistant diabetic rat hearts.. By immunohistochemistry and in situ hybridization, transforming growth factor-beta1 (TGF-beta1) expression increased in coronary vessels, the perivascular area, and cardiomyocytes in diabetic rat hearts. Increased expression of plasminogen activator inhibitor-1 (PAI-1) in coronary vessels and the perivascular area was evident in diabetic hearts. In contrast, diabetic hearts exhibited reduced activity and expression of MMP-2 and decreased expression of membrane type-1 MMP (MT1-MMP). Both intravascular and extravascular collagen type I and III immunoreactivity and fibrin deposition were seen in diabetic coronary vessels. These alterations were reversed to nondiabetic levels by the angiotensin II type 1 receptor blocker candesartan, which prevented the development of perivascular fibrosis observed after Masson's trichrome staining.. In addition to upregulation of PAI-1, downregulation of MMP-2 and MT1-MMP might play a crucial role in coronary matrix remodeling in insulin-resistant diabetes. These molecules appear to be regulated by angiotensin II via stimulation of TGF-beta1.

Topics: Angiotensin II; Animals; Collagen Type I; Collagen Type III; Coronary Vessels; Diabetes Mellitus, Type 2; Down-Regulation; Fibrin; Fibrosis; Insulin Resistance; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Rats; Rats, Inbred OLETF; Receptor, Melatonin, MT1; Transforming Growth Factor beta

To establish histologic criteria for a diagnosis of encapsulating peritoneal sclerosis (EPS), we investigated 69 peritoneal biopsy specimens histologically and immunohistochemically. The specimens included cases of EPS (n = 12), suspected cases of EPS without later manifestation (n = 5), cases of infectious peritonitis (n = 20), cases of ultrafiltration failure (n = 25), and peritoneum at the start of peritoneal dialysis (n = 7). For each specimen, we evaluated these histologic parameters: fibrin deposition, mesothelial denudation, interstitial fibrosis, peritoneal fibroblast swelling, perivascular bleeding capillary angiogenesis, microvascular sclerosis, and interstitial mononuclear cell infiltration. We also evaluated these immunohistochemical markers: macrophage migration inhibitory factor (MIF), fibroblast growth factor (FGF), FGF receptor 2 (FGFR2), alpha smooth muscle actin (alpha SMA), MIB1, and BCL2. The most characteristic histologic findings for EPS were fibrin deposition and fibroblast swelling. The presence of capillary angiogenesis and mononuclear cell infiltration were also associated with EPS. Expression of FGF, FGFR2, MIF, MIB1, and BCL2 in peritoneal fibroblasts was frequently observed in EPS. Our results suggest that fibrin deposition and peritoneal fibroblast activation or proliferation (or both) are useful findings for the early diagnosis of EPS. Careful histologic observation of the peritoneal biopsy after withdrawal of peritoneal dialysis is required for the early diagnosis and prevention of EPS.

Topics: Adult; Female; Fibrin; Fibrosis; Humans; Immunohistochemistry; Male; Middle Aged; Neovascularization, Pathologic; Peritoneal Dialysis, Continuous Ambulatory; Peritoneal Diseases; Peritoneum; Sclerosis

Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. The hearts of zebrafish with mutations in the Mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars. Thus, injury-induced cardiomyocyte proliferation in zebrafish can overcome scar formation, allowing cardiac muscle regeneration. These findings indicate that zebrafish will be useful for genetically dissecting the molecular mechanisms of cardiac regeneration.

Topics: Animals; Blood Coagulation; Bromodeoxyuridine; Cell Division; Collagen; Fibrin; Fibrosis; Gene Expression Regulation; Heart; Heart Injuries; Heart Ventricles; Mitosis; Models, Biological; Mutation; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Regeneration; Time Factors; Ventricular Function; Zebrafish; Zebrafish Proteins

The use of recombinant tissue plasminogen activator (r-TPA) has been advocated in the treatment of postsurgical fibrinous membrane formation following cataract surgery in adults. Its use in paediatric cases is not well documented.. A retrospective review of paediatric cataract extractions performed at Moorfields Eye Hospital between 1 January 1997 and 4 April 1999 was carried out.. Cataract extractions were performed in 37 patients, 22 in males 15 in females. Four (9.2%) underwent intracameral injection of 25 microg r-TPA. They were all females of Afro-Caribbean origin. The time to injection varied from 4-14 days, mean 7.2 days. Complete resolution of the fibrinous membrane was seen in all cases. There were no complications by the 3 month follow up.. r-TPA may be used safely and effectively at a dose of 25 microg for the treatment of severe fibrinous membranes following paediatric cataract extraction. It aided the visual recovery of the children and also allowed a reduced regimen of topical steroid therapy to be used postoperatively.

Topics: Anterior Chamber; Cataract Extraction; Child; Child, Preschool; Female; Fibrin; Fibrinolytic Agents; Fibrosis; Humans; Infant; Male; Postoperative Complications; Serine Endopeptidases; Tissue Plasminogen Activator; Visual Acuity

The histopathological characteristics of aneurysms obtained at autopsy or surgery 3 days to 54 months after being treated with Guglielmi detachable coils (GDCs) were assessed.. Seventeen aneurysms were obtained at autopsy and one was removed at surgery. Fourteen were examined histologically with the coils in situ. Naked coils embedded in an unorganized thrombus were found in those aneurysms that had been treated with coils within 1 week earlier. An incomplete replacement of the intraluminal blood clot by fibrous tissue and a partial membranous covering at the aneurysm orifice were observed in those aneurysms that had been treated with coils between 2 and 3 weeks prior to examination. One small aneurysm treated 6 weeks before harvesting showed formation of an endothelium-lined layer of connective tissue at the orifice. Collagen-rich vascularized tissue surrounding the coils was found in an aneurysm removed at surgery 54 months after coil implantation. Interestingly, six (50%) of 12 aneurysms (two small, three large, and one giant) that had been deemed 100% occluded on initial angiography showed tiny open spaces between the coils at the neck on gross examination.. Endothelialization of the aneurysm orifice following placement of GDCs can occur; however, it appears to be the exception rather than the rule. In large aneurysms the process of intraaneurysm clot organization seems to be delayed and incomplete; tiny open spaces between the coils and an incomplete membranous covering in the region of the neck are frequently encountered. Further longitudinal studies are required to establish the spectrum of healing profiles that may direct our efforts in modifying the GDC system to produce a more stable long-term result.

Topics: Adult; Aged; Cerebral Angiography; Collagen; Connective Tissue; Embolization, Therapeutic; Endothelium, Vascular; Female; Fibrin; Fibroblasts; Fibrosis; Follow-Up Studies; Humans; Intracranial Aneurysm; Longitudinal Studies; Macrophages; Male; Middle Aged; Surface Properties; Thrombosis; Wound Healing

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

Topics: Animals; Cells, Cultured; Coronary Thrombosis; Disease Models, Animal; Endothelium, Vascular; Fibrin; Fibrosis; Genetic Predisposition to Disease; Genotype; Hemostasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microcirculation; Myocardium; Thrombomodulin; Tissue Plasminogen Activator; Ultrasonography; Urokinase-Type Plasminogen Activator; Ventricular Dysfunction, Left

Cardiovascular implants of fresh autologous pericardium produced mixed results including fibrosis with retraction or thinning and dilatation. The reasons for these differences are unknown but may involve activation of cells intrinsic to the tissue implant. To better understand the behavior of autologous pericardial implants, we studied the outcomes of vital pericardium (fresh) versus ethanol-killed pericardium.. Fresh and ethanol-killed autologous pericardium was transplanted as a patch, a conduit, or a rectangular flap bisecting the lumen in the descending aorta of sheep. The implants, recovered at 1, 5, 10, 15, and 30 days, were evaluated macroscopically and microscopically and by immunohistologic studies.. Fresh implants showed good preservation with fibrin deposition on day 15. Microscopically, cells positive for alpha-actin and von Willebrand-related antigen appeared in the fibrin by day 10. By day 30 the flap was fibrotic and retracted whereas the patch and conduit retained their original appearance on the luminal aspect. An endothelium-like layer expressing von Willebrand-related antigen was present in the patch and conduit but absent in the flap. In contrast, the ethanol-killed implants were free of fibrin by day 10. By day 30, there were no signs of fibrosis or retraction, and a surface layer of cells expressing von Willebrand-related antigen, characteristic of endothelial cells, was present on all implants. All ethanol-killed implants were repopulated by host cells.. The transluminal flap is an interesting model for studying the behavior of intraluminal autologous pericardial cardiovascular implants. Killing of the pericardial implants alleviated the fibrosis and tissue retraction observed with fresh flap implants.

Topics: Actins; Animals; Aorta, Thoracic; Blood Vessel Prosthesis Implantation; Collagen; Dilatation, Pathologic; Endothelium, Vascular; Ethanol; Fibrin; Fibrosis; Fixatives; Follow-Up Studies; Immunohistochemistry; Neutrophils; Pericardium; Sheep; Surgical Flaps; Tissue Preservation; Transplantation, Autologous; von Willebrand Factor

This study was carried out to investigate interstitial fibrin and fibronectin deposition and subsequent myocardial connective tissue abnormalities in BALB/c-nu/+ (euthymic and normal T cell function) and BALB/c-nu/nu (athymic and T cell-deficient) mice. Both types of mice were inoculated with encephalomyocarditis virus and sacrificed periodically. Sections of the hearts were stained with haematoxylin-eosin, trichrome, lymphocyte subsets, silver impregnation, and fibrin or fibronectin. In addition, myocardial collagen concentration was measured. Interstitial fibrin and fibronectin appeared in parallel with inflammatory T lymphocytes and myocardial necrosis in the BALB/c-nu/+ mice. The changes increased until 14 days, subsequently decreasing with time. Interstitial fibrosis and abnormal reticulin fibres were absent until 7 days postinfection, and then increased with time until 60 days. In BALB/c-nu/nu mice, in contrast, although myocardial necrosis and fibrin-fibronectin deposition associated with immature T lymphocytes were evident on days 7 and 14, subsequent myocardial fibrosis and reticulin fibre abnormalities were minimal on days 30 and 60. In BALB/c-nu/+ mice, myocardial collagen concentration increased on day 30, but it did not in BALB/c-nu/nu mice. Thus, interstitial fibrin-fibronectin deposition resulting from virus-induced and T lymphocyte-mediated myocyte necrosis precedes the subsequent development of interstitial fibrosis and abnormal reticulin architectures in this model of murine myocarditis.

Topics: Animals; Cardiovirus Infections; Collagen; Encephalomyocarditis virus; Extracellular Matrix; Fibrin; Fibronectins; Fibrosis; Immunoenzyme Techniques; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Myocarditis; Myocardium; T-Lymphocytes

Peyronie's disease is a pathological fibrosis characterized by excessive deposition of collagen in the plaque. Although the etiology of Peyronie's disease is unknown, trauma has been hypothesized as the inciting event. In an effort to obtain more insight into the pathogenesis of Peyronie's disease plaque tissue was examined for collagen, elastic fiber, and fibrin content and distribution.. Plaque tissue specimens from 33 patients with Peyronie's disease, control penile tissue and nodular tissue from 8 patients with Dupuytren's contracture were analyzed histochemically for collagen staining and elastic fiber structure and distribution. Plaque tissue from 19 Peyronie's disease patients, control tissue and nodular tissue from Dupuytren's disease were also analyzed for the presence of fibrin by histochemical staining and immunoblotting.. Aberrantly stained collagen was detected in 32 of 33 plaque specimens (97%) and disrupted elastic fibers in 31 of the same specimens (94%). Fibrin deposition was detected histochemically in plaque tissue from 18 of 19 patients (95%) but it was not detectable in normal or scarred tunica from control patients. The presence of authentic fibrin accumulation in plaque tissue was confirmed by immunoblot analysis but fibrin was not detected in dermal tissue extracts from the same patient. Aberrant collagen staining and fibrin deposition were detected in nodular tissue from 7 of 8 Dupuytren's contracture patients (88%) and altered elastic fibers in 5 of the same patients (63%).. Deposition of fibrin in plaque tissue is consistent with the hypothesis that repetitive microvascular injury results in fibrin deposition in the tissue space and has served to provide insights into the pathophysiology of Peyronie's disease. We propose a model that accounts for the clinical and biological features of Peyronie's disease.

Topics: Adult; Aged; Collagen; Elastin; Fibrin; Fibrosis; Humans; Male; Middle Aged; Penile Induration

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Cytokines; Enalapril; Fibrin; Fibrinolysin; Fibrosis; Gene Expression Regulation, Enzymologic; Growth Substances; Imidazoles; In Situ Hybridization; Kidney; Male; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; RNA, Messenger; Tetrazoles; Thrombosis; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Vasoconstrictor Agents

The masseter and temporalis muscles were investigated ultrastructurally in 2 patients having fibrodysplasia ossificans progressiva (FOP). Results showed atrophy and necrosis of muscle fibres. Both cases contained cartilage which was calcified in the second case and was associated with degenerating chondrocytes. The blood vessels showed various changes, with haematoma formation and large fibrin deposits. Some of the fibrin deposits seen in the second case were surrounded with cartilage. This suggests that the cartilage probably forms as a reaction to an old haemorrhage. It is possible that the effect of the mutant gene found in FOP is on blood vessels rather than the normal regulatory mechanisms of the inducible osteogenic precursor cells. These degenerating blood vessels often result in haemorrhage and fibrin deposits; the fibrosis, cartilage or bone formation are probably secondary changes. Amianthoid fibres found in the tendon of the temporalis muscles of the second case, together with the other changes of fibrosis and cartilage formation, account for the severe restricted mouth opening suffered by these patients.

Topics: Adolescent; Adult; Arterioles; Calcinosis; Capillaries; Cartilage; Female; Fibrin; Fibrosis; Hematoma; Humans; Male; Masseter Muscle; Muscle Fibers, Skeletal; Muscular Atrophy; Mutation; Myositis Ossificans; Necrosis; Temporal Muscle; Tendons; Venules

To report unusual and heretofore unreported visually damaging manifestations of severe central serous chorioretinopathy.. Case studies.. Each of six male patients (average age, 40 years) had a form of severe central serous chorioretinopathy with at least one eye containing fibrin in the subretinal space that then developed into a subretinal fibrotic scar. Scar formation was followed by a tenting up of the macula, vascularization of the fibrosis (subretinal neovascularization), or a retinal pigment epithelial rip. Four of the seven eyes with subretinal fibrosis had severe visual loss (20/400 or worse).. Subretinal fibrin and other extracellular matrix molecules appear to stimulate the retinal pigment epithelium to undergo fibrous metaplasia, which results in subretinal fibrotic scar formation and other sequelae, all of which can lead to severe visual loss.

Topics: Adult; Body Fluids; Choroid Diseases; Exudates and Transudates; Fibrin; Fibrosis; Fluorescein Angiography; Fundus Oculi; Humans; Male; Middle Aged; Retina; Retinal Detachment; Retinal Diseases; Vision Disorders; Visual Acuity

Myocardial fibrosis is a characteristic late feature in cases of viral myocarditis that progress to dilated cardiomyopathy. However, the pathogenesis of the myocardial fibrosis in such cases is unknown. Prior studies have shown that in healing wounds and tumor stroma generation, interstitial fibrin deposition precedes the development of fibrosis. Therefore, interstitial fibrin deposition in the myocardium was investigated in a murine model of myocarditis in which dilated cardiomyopathy develops. Inbred male C3H/He mice inoculated with coxsackievirus B3 were killed 0, 3, 7, 14, 21, 30, and 60 days after infection. Paraffin sections of hearts were stained with hematoxylin-eosin, Masson's trichrome stain, and antibodies to fibrinogen/fibrin by use of an immunoperoxidase technique. Pretreatment of all mice with anticoagulants and antifibrinolytics 5 minutes before death was used to prevent artifactual fibrin deposition and fibrinolysis during tissue manipulation. Tissue fixation in formalin supplemented with acetic acid served to extract non-cross-linked fibrin, fibrinogen, and fibrinogen and fibrin degradation products, thus ensuring that clotted and cross-linked fibrin was the major immunoreactant. Myocardial fibrin deposition and fibrosis were each quantitated by computer-assisted image analysis. Myocardial fibrin deposition first appeared on day 3, was maximal on day 14, and disappeared by day 30. Conversely, myocardial fibrosis was not detectable until day 14 and was maximal at day 60. Thus, as in healing wounds and developing tumor stroma, fibrin deposition preceded fibrosis in this murine model of myocarditis that progresses to dilated cardiomyopathy.

Topics: Animals; Cardiomyopathy, Dilated; Coxsackievirus Infections; Eosine Yellowish-(YS); Fibrin; Fibrosis; Hematoxylin; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Staining and Labeling

It has been previously proposed that there is a primary microvascular abnormality in patients with systemic sclerosis. In this study using conventional light and electron microscopy, immunohistochemistry, and labelled adenosine uptake techniques, changes in the dermal microvasculature have been related to the various clinical stages of skin disease in systemic sclerosis. The earliest pathological changes are seen in clinically normal skin. They constitute changes in endothelial cell function and their consequences. Perivascular oedema is an early feature. With progression in the clinical disease, there is, at first, an inflammatory cell infiltrate into the dermis, particularly the papillary and mid-dermis, and platelet aggregation within vessels. Further clinical progression is associated with increasing dermal fibrosis, loss of adnexae, and vascular effacement. It is postulated that the recruitment of different types of mononuclear cells into the dermis is causally linked with the preceding endothelial cell dysfunction and the subsequent induction of fibroblast proliferation and collagen synthesis.

Topics: Adenosine; Adolescent; Adult; Aged; Autoradiography; Blood Vessels; Endothelium, Vascular; Female; Fibrin; Fibrosis; Humans; Immunohistochemistry; Male; Mast Cells; Microcirculation; Microscopy, Electron; Middle Aged; Scleroderma, Systemic; Skin

The first biocompatibility studies on the DuPont perfluorosulphonic acid polymer (Nafion) are presented. Presterilized samples of commercially cast and solution cast Nafion membranes were implanted subcutaneously, intraperitoneally and intravenously in male Sprague-Dawley rats. Scanning electron microscopy and histological examination of explanted samples and surrounding tissues reveal little, if any, evidence of acute or chronic foreign body inflammatory response. The fibrous capsules surrounding the implant remain nominally thin (less than 100 microns) after more than 3 months in situ, while the surrounding tissue remains well vascularized. Nafion polymer exhibits sufficient biocompatibility to make it a viable candidate for some implantable biosensor applications. It may, however, be necessary to compensate for the effect of the progression of fibrous encapsulation on sensor performance, particularly during the acute response stage.

Topics: Abdominal Muscles; Animals; Biosensing Techniques; Collagen; Connective Tissue; Feasibility Studies; Fibrin; Fibroblasts; Fibrosis; Fluorocarbon Polymers; Foreign-Body Reaction; Male; Materials Testing; Membranes, Artificial; Microscopy, Electron, Scanning; Prostheses and Implants; Rats; Rats, Inbred Strains; Surface Properties; Vena Cava, Inferior

We report a patient who developed severe intraocular fibrin formation following penetrating keratoplasty and vitrectomy surgery. The fibrin response worsened despite aggressive treatment with topical steroids. On the second postoperative day, 25 micrograms of intracameral tissue plasminogen activator was administered, resulting in rapid resolution of the fibrin response. The graft remained clear. We believe tissue plasminogen activator may be useful in selected cases of severe, recalcitrant postkeratoplasy fibrin formation.

Topics: Eye Diseases; Female; Fibrin; Fibrosis; Humans; Keratoplasty, Penetrating; Middle Aged; Tissue Plasminogen Activator; Vitrectomy

According to the conventional hypothesis and its variants, wound granulation tissue is formed by the proliferation and the migration of two closely cooperating but separated cell systems: the endothelial and the fibroblastic (including pericytes). While the elaborated theory of angiogenesis explains the former, there is not a similar theory concerning the latter. The recently proposed angiogenic hypothesis of repair and fibrosis unifies both cell systems by proposing endothelial origin for fibroblastic cells. It was formed on the basis of hyperplastic capillaries and vascular endothelium derived fibroblastic cells in chronic fibrotic diseases. The recent description of hyperplastic capillary sprouts in experimental fibrin clots confirms the validity of this hypothesis also in healing by primary and secondary intentions.

Topics: Angiogenesis Inducing Agents; Animals; Capillaries; Cell Differentiation; Cicatrix; Endothelium, Vascular; Fibrin; Fibroblasts; Fibrosis; Growth Substances; Humans; Hyperplasia; Neovascularization, Pathologic; Wound Healing