fibrin and Pulmonary-Fibrosis

Fibrosis causes irreversible damage to lung structure and function in restrictive lung diseases such as idiopathic pulmonary fibrosis (IPF). Extravascular coagulation involving fibrin formation in the intra-alveolar compartment is postulated to have a pivotal role in the development of pulmonary fibrosis, serving as a provisional matrix for migrating fibroblasts. Furthermore, proteases of the coagulation and plasminogen activation (plasminergic) systems that form and breakdown fibrin respectively directly contribute to pulmonary fibrosis. The coagulants, thrombin and factor Xa (FXa) evoke fibrogenic effects via cleavage of the N-terminus of protease-activated receptors (PARs). Whilst the formation and activity of plasmin, the principle plasminergic mediator is suppressed in the airspaces of patients with IPF, localized increases are likely to occur in the lung interstitium. Plasmin-evoked proteolytic activation of factor XII (FXII), matrix metalloproteases (MMPs) and latent, matrix-bound growth factors such as epidermal growth factor (EGF) indirectly implicate plasmin in pulmonary fibrosis. Another plasminergic protease, urokinase plasminogen activator (uPA) is associated with regions of fibrosis in the remodelled lung of IPF patients and elicits fibrogenic activity via binding its receptor (uPAR). Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. This review describes the mechanisms by which components of the two systems primarily involved in fibrin homeostasis contribute to interstitial fibrosis, with a particular focus on IPF. Selectively targeting the receptor-mediated mechanisms of coagulant and plasminergic proteases may limit pulmonary fibrosis, without the bleeding complications associated with conventional anti-coagulant and thrombolytic therapies.

Topics: Animals; Fibrin; Fibrinolysis; Humans; Plasminogen; Plasminogen Activators; Pulmonary 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

The primary function of the coagulation cascade is to promote hemostasis and limit blood loss in response to tissue injury. In addition, there is now considerable evidence that coagulation plays pivotal roles in orchestrating inflammatory and tissue repair responses via both the generation of fibrin and activation of the family of proteinase-activated receptors (PARs). Consequently, uncontrolled coagulation and PAR signaling responses have been shown to contribute to excessive inflammatory and fibroproliferative responses in the context of a broad range of conditions, including acute lung injury and fibrotic lung disease. In terms of the cellular origin of excessive coagulation activity in the context of lung injury, coagulation zymogens are principally thought to be derived from the circulation and locally activated via the extrinsic tissue factor-dependent coagulation pathway within the intraalveolar compartment. More recently, we have provided compelling evidence that several key coagulation zymogens are locally synthesized by the hyperplastic alveolar epithelium in pulmonary fibrosis. In terms of signaling receptors activated in response to the coagulation cascade, current evidence suggests a major role for PAR1 in influencing endothelial-epithelial barrier disruption, inflammatory cell recruitment, and collagen deposition in response to lung injury, whereas PAR2 signaling has been implicated mainly in mediating lung inflammatory responses. This article reviews current understanding of coagulation pathways in acute and fibrotic lung injury and expands on the scientific rationale for strategies that specifically target intraalveolar coagulation or PAR signaling responses.

Topics: Acute Lung Injury; Blood Coagulation; Blood Coagulation Factors; Fibrin; Fibrinolysis; Humans; Lung Injury; Peptide Hydrolases; Prothrombin; Pulmonary Alveoli; Pulmonary Fibrosis; Receptors, Proteinase-Activated; Signal Transduction; Thrombin

The mechanisms of pulmonary fibrosis are complex, and several hypotheses have been put forward to explain how fibrosis develops. It was long thought that inflammation was a key event in the process; however, this has recently been challenged. The inflammation hypothesis has led to the description of numerous inflammatory and profibrotic mediators in the pathogenesis of fibrosis. Inhibition of inflammation can attenuate fibrosis in animal models but is less successful in humans. More recently, an important role for epithelial injury, circulating mesenchymal precursor cells, epithelial-to-mesenchymal transition, and vascular remodeling have been described in various models of fibrosis. Many of the classic inflammatory and profibrotic mediators are important in these processes, as well. The development of effective therapies will require the understanding of the complex interplay of the various mediators and the mechanisms of remodeling.

Topics: Animals; Arachidonic Acid; Blood Coagulation Factors; Cytokines; Fibrin; Growth Substances; Humans; Inflammation; Inflammation Mediators; Lipids; Pulmonary Fibrosis

Lysyl oxidase (LO) initiates the first step in the crosslinking of collagens and elastin and has also been shown to function as a tumor suppressor. The purpose of the present work was to determine whether the products of a newly described LO-like gene (LOXL) that encodes a close homolog of LO, the LO-like (LOL) protein, is associated with extracellular matrix remodeling during fibrotic disorders. Specific antibody against LOL identified proteins of approximately 30, 42, 52 and 68 kd in various cells and in bovine aorta. These proteins were immunochemically distinct from the recombinant LO expressed by fibroblasts and from the bovine aorta LO. The LO gene (LOX) and LOXL were transiently up-regulated at early stages of liver granuloma development in Schistosoma mansoni-infected mice, although the peak of LOL mRNA synthesis preceded that of LO. LOL protein and LO were colocalized at sites of fibrogenesis in human lung fibrosis and in the stromal reaction of bronchiolo-alveolar carcinomas and of in situ ductal breast tumors. In conclusion, the LOL protein was identified as a secreted protein and localized in the extracellular matrix in active fibrotic diseases and in the early stromal reaction of breast cancer.

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Animals; Carcinoma, Ductal, Breast; Cattle; Cell Line; Female; Fibrin; HeLa Cells; Humans; Liver Diseases, Parasitic; Lung; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Peptide Fragments; Protein-Lysine 6-Oxidase; Pulmonary Fibrosis; RNA, Messenger; Schistosomiasis mansoni; Stromal Cells

Topics: Fibrin; Fibroblasts; Humans; Lung; Pneumonia; Pulmonary Alveoli; Pulmonary Fibrosis; Signal Transduction

Topics: Binding Sites; Collagen; Fibrin; Fibronectins; Humans; Lung; Macrophages; Pulmonary Fibrosis

To determine whether the delivery of recombinant truncated plasminogen activator inhibitor-1 (PAI-1) protein (rPAI-1(23)) would protect from the development of radiation-induced lung injury.. C57Bl/6 mice received intraperitoneal injections of rPAI-1(23) (5.4 μg/kg/d) or vehicle for 18 weeks, beginning 2 days before irradiation (IR) (5 daily fractions of 6 Gy). Cohorts of mice were followed for survival (n=8 per treatment) and tissue collection (n=3 per treatment and time point). Fibrosis in lung was assessed with Masson-Trichrome staining and measurement of hydroxyproline content. Senescence was assessed with staining for β-galactosidase activity in lung and primary pneumocytes.. Hydroxyproline content in irradiated lung was significantly reduced in mice that received rPAI-1(23) compared with mice that received vehicle (IR+vehicle: 84.97 μg/lung; IR+rPAI-1(23): 56.2 μg/lung, P=.001). C57Bl/6 mice exposed to IR+vehicle had dense foci of subpleural fibrosis at 19 weeks, whereas the lungs of mice exposed to IR+rPAI-1(23) were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-1(23) treatment in primary pneumocyte cultures and in lung at multiple time points after IR.. These studies identify that rPAI-1(23) is capable of preventing radiation-induced fibrosis in murine lungs. These antifibrotic effects are associated with increased fibrin metabolism, enhanced matrix metalloproteinase-3 expression, and reduced senescence in type 2 pneumocytes. Thus, rPAI-1(23) is a novel therapeutic option for radiation-induced fibrosis.

Topics: Alveolar Epithelial Cells; Animals; Cell Proliferation; Cellular Senescence; Collagen; Cytokines; Female; Fibrin; Hydroxyproline; Lung; Matrix Metalloproteinase 3; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis; Radiation Pneumonitis; Real-Time Polymerase Chain Reaction; Recombinant Proteins

Patients with pulmonary fibrosis often have low vitamin D levels, the effects of which are largely unknown. We here report that early vitamin D supplementation significantly reduced the severity of pulmonary fibrosis and inflammatory cell accumulationin in the bleomycin-induced pulmonary fibrosis mouse model on supplementary days 14, 21 and 28 (P < 0.001). Vitamin D supplementation also prevented some ultrastructural changes in response to bleomycin administration, including basement membrane thickening, interstitial fibrin deposition and microvilli flattening or disappearance on days 14, 21 and 28, and lamellar body swelling or vacuolation on days 21 and 28. The bleomycin group had rising hydroxyproline level on days 14, 21 and 28, whereas the vitamin D treatment group showed consistently lower hydroxyproline level but still higher than that of the control group (P < 0.001). Our immunohistochemistry and densitometry analyses showed less staining for α-smooth muscle actin, a myofibroblast marker, in the vitamin D group compared to the bleomycin group (P < 0.001). Thus, vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation. These data further our understanding of the roles of vitamin D in pulmonary fibrogenesis and in the treatment of pulmonary fibrosis.

Topics: Animals; Bleomycin; Dietary Supplements; Fibrin; Hydroxyproline; Male; Mice; Pulmonary Fibrosis; Vitamin D

Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) deficient mice in the FVB/n strain exhibit fatal chronic pulmonary fibrotic disease. The illness occurs in the absence of a detectable pro-inflammatory event. PECAM-1 is vital to the stability of vascular permeability, leukocyte extravasation, clotting of platelets, and clearance of apoptotic cells. We show here that the spontaneous development of fibrotic disease in PECAM-1 deficient FVB/n mice is characterized by early loss of vascular integrity in pulmonary capillaries, resulting in spontaneous microbleeds. Hemosiderin-positive macrophages were found in interstitial spaces and bronchoalveolar lavage (BAL) fluid in relatively healthy animals. We also observed a gradually increasing presence of hemosiderin-positive macrophages and fibrin deposition in the advanced stages of disease, corresponding to the accumulation of collagen, IL-10 expression, and myofibroblasts expressing alpha smooth muscle actin (SMA). Together with the growing evidence that pulmonary microbleeds and coagulation play an active part in human pulmonary fibrosis, this data further supports our hypothesis that PECAM-1 expression is necessary for vascular barrier function control and regulation of homeostasis specifically, in the pulmonary environment.

Topics: Animals; Bleeding Time; Disease Models, Animal; Fibrin; Hemorrhage; Hemosiderin; Interleukin-10; Macrophages, Alveolar; Mice; Mice, Inbred Strains; Myofibroblasts; Platelet Endothelial Cell Adhesion Molecule-1; Pulmonary Fibrosis

Plasma plasminogen activator inhibitor-1 (PAI-1) level rises during sepsis and confers a worse prognosis. PAI-1 participation to sepsis has been poorly documented and was mainly associated with fibrin deposits. Beside fibrin deposits, increased tissue PAI-1 expression may contribute to the poor outcome of endotoxemia through other mechanisms.. During lipopolysaccharide (LPS) challenge, the role of PAI-1 in the early phase of inflammation was examined in the lungs of transgenic mice that either overexpress or lack the PAI-1 gene (PAI-1Tg or PAI-1(-/-)).. Analysis of leukocytes revealed that neutrophil and macrophage infiltrations did not differ for PAI-1Tg and wild-type (WT) mice. Remarkably, CD25+ lymphocyte infiltration was totally blunted in PAI-1Tg lungs and inversely correlated with fibrin depositions. In parallel, mRNA levels of the regulatory T cell (Treg) markers FoxP3, CTLA-4, and GITR were significantly lower in PAI-1Tg than in WT lungs after LPS challenge. These data are supported by opposite results in PAI-1(-/-) lungs. The systemic compartments (spleen and peripheral blood) showed no decrease in CD25+, CD4+ CD25+ lymphocytes, and Treg markers in PAI-1Tg mice after LPS injection compared with WT mice. In addition, plasma and lung concentrations of interleukin-6 (IL-6) and macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly higher in PAI-1Tg mice than WT mice.. Our results suggest that chronic tissue PAI-1 overexpression influences the early phase of the inflammatory response during endotoxemia through the control of T lymphocyte traffic.

Topics: Animals; Antigens, CD; Antigens, Differentiation; Chemokine CCL3; Chemotaxis, Leukocyte; CTLA-4 Antigen; Disease Models, Animal; Endotoxemia; Fibrin; Forkhead Transcription Factors; Glucocorticoid-Induced TNFR-Related Protein; Immunity, Innate; Inflammation; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Interleukin-6; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Knockout; Mice, Transgenic; Neutrophils; Pulmonary Fibrosis; Receptors, Nerve Growth Factor; Receptors, Tumor Necrosis Factor; RNA, Messenger; Serpin E2; Serpins; T-Lymphocytes; T-Lymphocytes, Regulatory; Time Factors; Up-Regulation

Decreased fibrinolytic function favors the development of pulmonary fibrosis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a strong suppressor of fibrinolysis, but its role in lung fibrosis is unknown. Therefore, we compared bleomycin-induced lung fibrosis in TAFI-deficient, heterozygous, and wild-type mice. The animals were sacrificed 21 days after bleomycin administration, and markers of lung fibrosis and inflammation were measured. The bronchoalveolar lavage fluid levels of total protein, neutrophil proteases (elastase, myeloperoxidase), cytokines (tumor necrosis factor-alpha, interleukin-13), chemokine (monocyte chemoattractant protein-1), coagulation activation marker (thrombin-antithrombin complex), total soluble collagen, and growth factors (platelet-derived growth factor, transforming growth factor-beta1, granulocytic-macrophage growth factor) were significantly decreased in knockout mice compared to wild-type mice. Further, histological findings of fibrosis, fibrin deposition, and hydroxyproline and collagen content in the lung were significantly decreased in knockout mice compared to wild-type mice. Depletion of fibrinogen by ancrod treatment led to equalization in the amount of fibrosis and collagen deposition in the lungs of knockout and wild-type mice. No difference was detected in body temperature or arterial pressure between the different mouse phenotypes. These results suggest that the anti-fibrinolytic activity of TAFI promotes lung fibrosis by hindering the rate at which fibrin is degraded.

Topics: Animals; Antithrombin III; Bleomycin; Blood Pressure; Body Temperature; Bronchoalveolar Lavage Fluid; Carboxypeptidase B2; Collagen; Cytokines; Fibrin; Fibrinogen; Growth Substances; Hydroxyproline; Lung; Mice; Mice, Knockout; Pancreatic Elastase; Peptide Hydrolases; Peroxidase; Pulmonary Fibrosis

Topics: Fibrin; Fibrinolytic Agents; Humans; Lung; Pneumonia; Pulmonary Fibrosis; Respiratory Distress Syndrome; Thrombosis; Time Factors

Considerable confusion exists regarding the proper classification of idiopathic eosinophilic pneumonia (IEP). Furthermore, there are no reports describing the clinicopathological differences between the various forms of eosinophilic pneumonias.. The histological findings in acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP) were examined and the clinical and radiological features were contrasted with them.. Radiologically, ground glass opacity and interlobular septal thickening were characteristic of the AEP cases, while air space consolidation was seen in all CEP cases. Histologically, interstitial oedema and fibrin deposition were prominent in the AEP cases. Type II cells were detached from the alveolar walls, although the basal lamina was predominantly intact. In CEP, in addition to cellular infiltration, there was prominent intraluminal fibrosis. Disruption of the basal lamina was observed and nests of intraluminal fibrosis were directly adjacent and connected to the alveolar walls.. An essential histological difference between AEP and CEP is the severity of basal lamina damage and the amount of subsequent intraluminal fibrosis. In AEP particularly, these findings explain the radiographical findings, as well as the rapid and complete improvement noted in such cases.

Topics: Acute Disease; Adolescent; Adult; Aged; Basement Membrane; Biopsy; Bronchoalveolar Lavage; Chronic Disease; Female; Fibrin; Humans; Lung; Male; Middle Aged; Pulmonary Alveoli; Pulmonary Edema; Pulmonary Eosinophilia; Pulmonary Fibrosis; Radiography, Thoracic; Retrospective Studies; Tomography, X-Ray Computed

The contribution of plasma protein(s) to the stabilization of fibroids formed in rat lungs exposed to acute silica dust inhalation was examined. Antibodies against component proteins of the nodules remaining insoluble in 2% SDS, 10M urea and 40 mM sulfhydryl reagents under prolonged boiling conditions were raised in rabbits and used to capture plasma proteins, which were identified by 2D-gel electrophoresis and MALDI-TOF analysis. The silica particles were encapsulated with extracellular protein composites whose amino acid compositions showed high levels of alanine, i.e., above those of glycine and proline, a building block of collagen. Antibody-captured plasma proteins showed the dominant presences of fibrinogen, albumin, and prealbumin (transthyretin), and other minor proteins, which included alpha-1-protease inhibitor, contraspin-like protease inhibitor, cathepsin B, etc. The presence of the N(epsilon)-(gamma-glutamyl) lysine isopeptide bond in the nodules was evidenced by direct chemical methods and by immunoreactivity for anti-isopeptide bonds. Immunostaining of affected lung tissue and of the fibroid regions showed elevated levels of transglutaminase (TGase) E and plasma factor XIII (F-XIII), but showed no reactivity towards other TGases. These findings suggest that the silica encapsulated nodules are a mixture of extracellular proteins that include collagen type I, fibrin and transthyretin, which is stabilized by TGase catalyzed crosslinking between plasma and extracellular proteins during fibrosis to eventually form insoluble nodules.

Topics: Air Pollutants, Occupational; Animals; Blood Proteins; Collagen Type I; Cross-Linking Reagents; Fibrin; Inhalation Exposure; Intubation, Intratracheal; Male; Peptide Mapping; Prealbumin; Protein Binding; Proteomics; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Silicon Dioxide; Silicosis; Transglutaminases

Topics: Cell Line, Tumor; Epithelial Cells; Fibrin; Humans; Interleukin-1; Interleukin-1beta; Peptide Fragments; Pulmonary Alveoli; Pulmonary Fibrosis; Urokinase-Type Plasminogen Activator; Wound Healing

Intra-alveolar fibrin is formed following lung injury and inflammation and may contribute to the development of pulmonary fibrosis. Fibrin turnover is altered in patients with pulmonary fibrosis, resulting in intra-alveolar fibrin accumulation, mainly due to decreased fibrinolysis. Alveolar type II epithelial cells (AEC) repair the injured alveolar epithelium by migrating over the provisional fibrin matrix. We hypothesized that repairing alveolar epithelial cells modulate the underlying fibrin matrix by release of fibrinolytic activity, and that the degree of fibrinolysis modulates alveolar epithelial repair on fibrin. To test this hypothesis we studied alveolar epithelial wound repair in vitro using a modified epithelial wound repair model with human A549 alveolar epithelial cells cultured on a fibrin matrix. In presence of the inflammatory cytokine interleukin-1beta, wounds increase by 800% in 24 hours mainly due to detachment of the cells, whereas in serum-free medium wound areas decreases by 22.4 +/- 5.2% (p < 0.01). Increased levels of D-dimer, FDP and uPA in the cell supernatant of IL-1beta-stimulated A549 epithelial cells indicate activation of fibrinolysis by activation of the plasmin system. In presence of low concentrations of fibrinolysis inhibitors, including specific blocking anti-uPA antibodies, alveolar epithelial repair in vitro was improved, whereas in presence of high concentrations of fibrinolysis inhibitors, a decrease was observed mainly due to decreased spreading and migration of cells. These findings suggest the existence of a fibrinolytic optimum at which alveolar epithelial repair in vitro is most efficient. In conclusion, uPA released by AEC alters alveolar epithelial repair in vitro by modulating the underlying fibrin matrix.

Topics: alpha-2-Antiplasmin; Antibodies; Antifibrinolytic Agents; Cell Line, Tumor; Cell Movement; Cell Shape; Dose-Response Relationship, Drug; Epithelial Cells; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Interleukin-1; Pulmonary Alveoli; Pulmonary Fibrosis; Time Factors; Tranexamic Acid; Urokinase-Type Plasminogen Activator; Wound Healing

Acute and chronic pulmonary diseases are characterized by impaired fibrinolytic activity within the lung. To determine the role of the fibrinolytic system in regulating the pathologies associated with lung injury, we examined the effect of bleomycin, an agent that induces the development of pulmonary fibrosis, in mice deficient for plasminogen (Pg(-)(/-)), urokinase (u-PA(-)(/-)), urokinase receptor (u-PAR(-)(/-)), or tissue plasminogen activator (t-PA(-)(/-)), and in control wild-type (WT) mice. Pg(-)(/-) and t-PA(-)(/-) mice demonstrated an enhanced increase in lung collagen content relative to that observed in WT mice. Levels in u-PA(-)(/-) and u-PAR(-)(/-) mice were similar to those in WT mice. Histological analysis 14 days after lung injury confirmed enhanced interstitial fibrosis in Pg(-)(/-), u-PA(-)(/-), and t-PA(-)(/-) mice relative to WT and u-PAR(-)(/-) mice. Areas of pulmonary hemorrhage were observed in bleomycin-treated WT mice and not in Pg(-)(/-), u-PA(-)(/-), and u-PAR(-)(/-) mice or saline controls. Instead, extensive areas of fibrosis were present throughout the lungs of bleomycin-treated Pg(-)(/-) and u-PA(-)(/-) mice. A mixed phenotype (hemorrhage and fibrosis) was observed in t-PA(-)(/-) and Pg(+/-) mice. Hemosiderin-laden macrophages were abundant in the lungs of mice exhibiting hemorrhage and these mice were prone to an early death. Enhanced macrophage levels in the lungs and activation of matrix metalloelastase (MMP-12) were found in mice with a hemorrhage phenotype. The results of these studies indicate a role for the fibrinolytic system in acute lung injury and suggests that intra-alveolar hemorrhage is the result of basement membrane degradation through cell-mediated u-PA activation of Pg with possible involvement of matrix metalloproteinases. Absence of these two components of the fibrinolytic system, either urokinase or plasminogen, results in accelerated fibrosis.

Topics: Animals; Bleomycin; Blood Coagulation Factors; Collagen; Enzyme Activation; Female; Fibrin; Genotype; Leukocyte Count; Lung; Male; Matrix Metalloproteinase 12; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Plasminogen; Pulmonary Fibrosis; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

The mesothelial lining of the pleura and malignant mesothelioma promote fibrin deposition in pleural injury or neoplasia via expression of tissue factor (TF). It was hypothesized that these cells might also regulate intrapleural coagulation by elaborating TF pathway inhibitor (TFPI). TFPI activity and antigen in pleural fluids were assayed from patients with congestive heart failure (CHF), pneumonia, empyema, metastatic pleural cancer and malignant mesothelioma. The authors also assessed expression of TF and TFPI messenger ribonucleic acid (mRNA) as well as TFPI activity and antigen by human pleural mesothelial cells, malignant mesothelioma cells (MS-1 cell line) and human lung fibroblasts. Immunohistochemical analyses of normal, fibrotic, and neoplastic pleura were performed to determine whether TFPI antigen was expressed in vivo. The study revealed that TFPI was present in transudates from patients with CHF and exudative pleural effusions from patients with pneumonia, empyema or pleural carcinoma. TFPI mRNA, activity and antigen were expressed by pleural mesothelial cells, MS-1 cells and lung fibroblasts. Cytokines and serum stimulated a significant early increase in TF mRNA levels with minimal enhancement of TFPI mRNA, activity and antigen levels. TFPI antigen was found in normal, fibrotic and neoplastic pleural tissues. The current observations indicate that tissue factor pathway inhibitor is locally expressed in pleural disease, but that it does not prevent the development of a prothrombotic environment favouring local fibrin deposition in pleural inflammation or cancer.

Topics: Blotting, Northern; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lipoproteins; Male; Mesothelioma; Pleura; Pleural Neoplasms; Pulmonary Fibrosis; RNA, Messenger; Thromboplastin

Bronchoalveolar lavage fluids (BALF) from patients with hypersensitivity pneumonitis (HP; n = 35), idiopathic pulmonary fibrosis (IPF, n = 41) and sarcoidosis (SARC, n = 48) were investigated for alterations in the alveolar hemostatic balance. Healthy individuals (n = 21) served as Controls. Procoagulant activity (PCA), tissue factor (TF) activity and F VII activity were assessed by means of specific recalcification assays. The overall fibrinolytic activity (FA) was measured using the (125)I-labeled fibrin plate assay. Fibrinopeptide A (FP-A), D-Dimer, plasminogen activators (PA) of the urokinase (u-PA) or tissue type (t-PA), PA-inhibitor I (PAI-1) and alpha2-antiplasmin (alpha2-AP) were determined by ELISA technique. As compared to Controls, all groups with interstitial lung disease (ILD) displayed an increase in BALF PCA by approximately one order of magnitude, and this was ascribed to enhanced TF activity by >98%. Accordingly, F VII-activity was increased in all ILD groups, and elevated FP-A levels were noted. There was no significant difference in procoagulant activities between the different ILD entities, but the increase in TF was significantly correlated with deterioration of lung compliance. Overall fibrinolytic activity did not significantly differ between ILD entities and Controls, although some reduction in IPF subjects was observed. Nevertheless, changes in the profile of the different pro- and antifibrinolytic compounds were noted. U-PA, but not t-PA levels were significantly reduced in all ILD groups. alpha2-AP was markedly elevated throughout, whereas PAI-1 levels were lowered. As a balance of

Topics: Adolescent; Adult; Aged; Alveolitis, Extrinsic Allergic; Antifibrinolytic Agents; Blood Coagulation Factors; Bronchoalveolar Lavage Fluid; CD4-CD8 Ratio; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Hemostatics; Humans; Lung Compliance; Lung Diseases, Interstitial; Lymphocyte Count; Male; Middle Aged; Neutrophils; Pulmonary Fibrosis; Sarcoidosis; Thromboplastin

We investigated the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Bronchoalveolar lavage (BAL) fluid was obtained from 22 patients with IPF, and the levels of TF and TFPI antigen were measured by ELISA. The TF and TFPI levels in BAL fluid supernatant were significantly higher in IPF patients than in normal controls. In addition, both levels were significantly higher in advanced cases than in nonadvanced cases. There was a significant correlation between the TF and TFPI levels. Localization of TF and TFPI antigens was investigated by immunohistochemical staining. Both antigens were mainly localized in hyperplastic cuboidal epithelial cells, suggesting that the widespread distribution of these cells contributed to the increase of TF and TFPI antigen levels in the lungs of IPF patients. To assess whether TF activity is counterbalanced by TFPI in the lungs of IPF patients, we examined procoagulant activity and TF activity. It was found, however, that both procoagulant and TF activities were significantly higher in the BAL fluid supernatant of IPF patients than in that of normal controls, which suggested that TFPI was actually increased, but the increase was insufficient to counterbalance TF, leading to the development of a hypercoagulable state in the lungs of IPF patients.

Topics: Adult; Aged; Anticoagulants; Antigens; Blood Coagulation Tests; Bronchoalveolar Lavage Fluid; Epithelial Cells; Female; Fibrin; Fibrinolytic Agents; Humans; Immunohistochemistry; Lipoproteins; Lung; Male; Middle Aged; Pulmonary Fibrosis; Regression Analysis; Serine Proteinase Inhibitors; Thrombophilia; Thromboplastin

Mice deleted for the plasminogen activator inhibitor-1 (PAI-1) gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. We hypothesized that PAI-1 deficiency reduces fibrosis by promoting plasminogen activation and accelerating the clearance of fibrin matrices that accumulate within the damaged lung. In support of this hypothesis, we found that the lungs of PAI-1(-/-) mice accumulated less fibrin after injury than wild-type mice, due in part to enhanced fibrinolytic activity. To further substantiate the importance of fibrin removal as the mechanism by which PAI-1 deficiency limited bleomycin-induced fibrosis, bleomycin was administered to mice deficient in the gene for the Aalpha-chain of fibrinogen (fib). Contrary to our expectation, fib(-/-) mice developed pulmonary fibrosis to a degree similar to fib(+/-) littermate controls, which have a plasma fibrinogen level that is 70% of that of wild-type mice. Although elimination of fibrin from the lung was not in itself protective, the beneficial effect of PAI-1 deficiency was still associated with proteolytic activity of the plasminogen activation system. In particular, inhibition of plasmin activation and/or activity by tranexamic acid reversed both the accelerated fibrin clearance and the protective effect of PAI-1 deficiency. We conclude that protection from fibrosis by PAI-1 deficiency is dependent upon increased proteolytic activity of the plasminogen activation system; however, complete removal of fibrin is not sufficient to protect the lung.

Topics: Animals; Antifibrinolytic Agents; Bleomycin; Bronchoalveolar Lavage Fluid; Capillary Permeability; Collagen; Female; Fibrin; Fibrinogen; Fibrinolysin; Genotype; Kinetics; Lung; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis; Survival Analysis; Tranexamic Acid

Topics: Animals; Bleomycin; Disease Models, Animal; Fibrin; Fibrinogen; Fibrinolysin; Gene Deletion; Humans; Mice; Mice, Knockout; Plasminogen; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis

Intra-alveolar deposition of exudated plasma proteins is a hallmark of acute and chronic inflammatory lung diseases. In particular, fibrin and fibronectin may provide a primary matrix for fibrotic lung remodeling in the alveolar compartment. The present study was undertaken to explore the effect of two surfactant preparations on the incorporation of fibronectin into fibrin. We observed that surfactant phospholipids are associated with insoluble fibrin, factor XIIIa-cross-linked fibrin, and cross-linked fibrin with incorporated fibronectin. Factor XIIIa-mediated binding of fibronectin to fibrin was noticeably altered in the presence of surfactant. Coincubation with two different commercially available surfactants but not with dipalmitoylphosphatidylcholine alone resulted in a reduction of fibronectin incorporation into fibrin clots by approximately one-third. This effect was not dependent on the calcium concentration. We conclude that 1) factor XIIIa-cross-linked fibrin-fibronectin is able to incorporate surfactant phospholipids in amounts comparable to fibrin clots without fibronectin and 2) the binding of fibronectin to fibrin is partially inhibited in the presence of pulmonary surfactant.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Cattle; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrinogen; Fibronectins; Kinetics; Pulmonary Fibrosis; Pulmonary Surfactants; Swine; Transglutaminases

Although abnormalities of alveolar fibrin turnover have been reported to play a role in the development of idiopathic pulmonary fibrosis (IPF), the pathophysiological relevance remains unclear. We therefore investigated the localization of tissue factor (TF) and fibrin deposition in patients with IPF using immunohistochemistry and compared the results with those from patients who had interstitial pneumonia associated with systemic sclerosis (IP-SSc) and idiopathic bronchiolitis obliterans with organizing pneumonia (BOOP). Expression of TF-mRNA was also assessed, using in situ hybridization with a digoxigenin-labeled cRNA probe. In patients with IPF, IP-SSc, and idiopathic BOOP, the TF antigen was positively stained in type II pneumocytes and in some alveolar macrophages. The fibrin antigen was stained in the type II pneumocytes and the adjacent area. Tissue factor-mRNA was expressed in the type II pneumocytes and in some alveolar macrophages. Neither TF antigens nor TF-mRNA were detected in the normal lung. These results indicate that type II pneumocytes are a major source of TF, suggesting that TF production in these cells is closely related to fibrin deposition in the lungs of people with these diseases.

Topics: Base Sequence; Biopsy; Cryptogenic Organizing Pneumonia; DNA Primers; Fibrin; Humans; Immunohistochemistry; In Situ Hybridization; Lung; Lung Neoplasms; Molecular Sequence Data; Polymerase Chain Reaction; Pulmonary Fibrosis; RNA, Messenger; Scleroderma, Systemic; Thromboplastin

Fibrosis results when myofibroblasts invade the wound fibrin provisional matrix. Extracellular matrix receptors on the cell surface mediate cell adhesion, migration, and invasion. Recent work with transformed cells indicates that these cells use the cell surface matrix receptor CD44 for migration and invasion. In this study, we examine whether lung fibroblasts, isolated from patients dying with acute alveolar fibrosis, use CD44 to invade a fibrin matrix. Consistent with a role for CD44 in mediating fibroblast invasion and subsequent tissue fibrosis, immunohistochemical analysis of lung tissue from patients who died from acute alveolar fibrosis after lung injury reveals CD44-expressing mesenchymal cells throughout newly formed fibrotic tissue. PCR, Western, and immunoprecipitation analysis demonstrate that the 85-kD CD44 isoform is expressed by acute lung injury fibroblasts. Consistent with a role in mediating matrix adhesion and migration ultrastructurally, CD44 was found uniformly over the cell surface and was found densely labeling filopodia and lamellipodia, highly motile structures involved in cell migration. To determine if lung injury fibroblasts use CD44 to invade fibrin, a fibrin gel model of fibrosis was used. By blocking the function of CD44 with monoclonal antibodies, fibroblast invasion into a fibrin matrix was inhibited. To examine the mechanism by which CD44 mediates fibroblast invasion, the role of CD44 in fibroblast migration and adhesion was evaluated. Anti-CD44 antibody blocked fibroblast migration on the provisional matrix proteins fibronectin, fibrinogen, and hyaluronic acid. Additionally, fibroblast CD44 mediated adhesion to the provisional matrix proteins fibronectin, fibrin, and hyaluronic acid, but not to laminin, a component of the basement membrane. These findings support the hypothesis that fibroblast CD44 functions as an adhesion receptor for provisional matrix proteins and is capable of mediating fibroblast migration and invasion of the wound provisional matrix resulting in the formation of fibrotic tissue.

Topics: Cell Adhesion; Cell Movement; Cells, Cultured; Fibrin; Fibroblasts; Humans; Hyaluronan Receptors; Hyaluronic Acid; Immunohistochemistry; Pulmonary Fibrosis; Respiratory Distress Syndrome; RNA, Messenger

Bleomycin lung injury in mice leads to an acute alveolitis followed by a fibroproliferative response characterized by the accumulation of extracellular matrix. Because distinct regions of the fibrin(ogen) molecule have unique in vitro biological effects on cells, we quantified, localized, and biochemically characterized the molecular form of extravascular fibrin(ogen) in methoxyflurane anesthetized, bleomycin-injured mice. Bleomycin or saline (controls) was administered intratracheally, and lung tissue was harvested and analyzed at several times thereafter. Immunoreactive fibrin tissue content increased to a maximal 50-fold over controls in a temporal and spatial pattern paralleling that of alveolitis and maximal fibroproliferation. The generation of gamma-gamma-chain dimers and alpha-chain polymers, together with the loss of free alpha- and gamma-chains, indicates that the fibrin is predominantly covalently cross-linked. In fibroproliferative-phase lungs, the fibrin fibrils are branched and colocalize with those of collagen at the electron microscopic level. These observations strongly suggest that fibrin is a significant molecular effector of the in vivo fibroproliferative response after lung injury.

Topics: Animals; Bleomycin; Fibrin; Fibrinogen; Immunoenzyme Techniques; Lung Diseases; Mice; Mice, Inbred C57BL; Molecular Weight; Pulmonary Fibrosis

Bleomycin-induced lung injury is an established murine model of human pulmonary fibrosis. Although procoagulant molecules (e.g., tissue factor [TF]) and fibrinolytic components (e.g., urokinase [u-PA] and type 1 plasminogen activator inhibitor [PAI-1]) have been detected in alveolar fluid from injured lungs, the origin of these molecules remains unknown. We therefore examined the expression of procoagulant and fibrinolytic components in relation to the distribution of parenchymal fibrin in bleomycin-injured lungs. Extravascular fibrin localized to the alveolar and extracellular matrix in injured lung tissue. Injured lung tissue extracts contained elevated levels of PAI-1 activity and decreased levels of u-PA activity. Whole lung PAI-1 and TF mRNAs were dramatically induced by lung injury. In situ hybridization of injured lungs revealed that PAI-1, u-PA, and TF mRNAs were induced within the fibrin-rich fibroproliferative lesions, primarily in fibroblast-like and macrophagelike cells, respectively, while TF mRNA was also induced in perilesional alveolar cells. Taken together, these observations suggest that the induction of PAI-1 and TF gene expression plays and important role in the formation and persistence of extracellular fibrin in bleomycin injured murine lungs.

Topics: Animals; Bleomycin; Disease Models, Animal; Female; Fibrin; Fibrinolysis; Gene Expression; In Situ Hybridization; Lung; Mice; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis; RNA, Messenger; Thromboplastin; Time Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Alveolar fibrin deposition is prominent in diffuse alveolar damage, the morphologic hallmark of the adult respiratory distress syndrome. To determine if a persistent abnormality of fibrin clearance occurs in the alveolar compartment during evolving diffuse alveolar damage, we characterized abnormalities of fibrin turnover in serial bronchoalveolar lavage specimens from two baboon models: a) diffuse alveolar damage induced by 80% oxygen and bronchoscopic seeding of Pseudomonas aeruginosa; and b) a more fulminant form of diffuse alveolar damage induced by bronchoscopic seeding of Pseudomonas and the infusion of oleic acid.. Lavage procoagulant activity, due mainly to tissue factor associated with Factor VII, was increased and exceeded regulation by extrinsic pathway inhibitor in both models. Fibrinolytic activity was transiently diminished in baboons with evolving diffuse alveolar damage induced by oleic acid/Pseudomonas, but was preserved after 80% oxygen/Pseudomonas. Concentrations of plasminogen activator inhibitor-2 did not increase in lavage specimens obtained during evolving diffuse alveolar damage. Concentrations of alpha 2 antiplasmin and plasminogen activator inhibitor-1 tended to be higher in the lavage of oleic acid/Pseudomonas baboons with low fibrinolytic activity. Immunohistochemical analyses showed that tissue factor was distributed along the alveolar surface of controls and baboons with diffuse alveolar damage. Alveolar fibrin deposition was increased, by morphometric analyses, in both models.. These data indicate that while increased procoagulant activity is characteristic of evolving diffuse alveolar damage and favors alveolar fibrin deposition, fibrinolytic activity may be transiently diminished or remain intact during evolving diffuse alveolar damage in baboons.

Topics: alpha-2-Antiplasmin; Animals; Bronchoalveolar Lavage Fluid; Bronchoscopy; Disease Models, Animal; Evaluation Studies as Topic; Fibrin; Fibrinolysis; Immunohistochemistry; Metabolic Clearance Rate; Oleic Acid; Oleic Acids; Oxygen; Papio; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Pseudomonas aeruginosa; Pulmonary Fibrosis; Respiratory Distress Syndrome; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Idiopathic bronchiolitis obliterans-organizing pneumonia (BOOP) is characterized by air space fibrosis of unknown origin. Clinical resolution under steroid treatment suggests the removal of the fibrotic lesion. Open lung biopsies of four patients with idiopathic BOOP were studied by immunochemistry and electron microscopy. Three distinct cell-matrix patterns of intra-alveolar bud were found to represent the sequential evolution of the fibrotic process: fibrinoid inflammatory cell clusters in which immunoglobulins and procoagulant factors (fibrinogen, factors VII and X) were identified; fibroinflammatory buds in which desmin-containing fibroblasts were observed migrating, proliferating, and secreting matrix proteins; fibrotic buds in which myofibroblasts organized a loose connective matrix predominantly composed of fibronectin and type III collagen. Extending forms of fibrotic buds may join contiguous alveoli. Fibrotic bud remodeling ability is correlated to the nature and organization of the matrix components but the factors permitting intra-alveolar matrix degradation must be characterized.

Topics: Blood Coagulation Factors; Bronchiolitis Obliterans; Collagen; Fibrin; Fibrinogen; Fibronectins; Humans; Immunohistochemistry; Pneumonia; Pulmonary Alveoli; Pulmonary Fibrosis

Fibrin deposition is prominent in the course of several forms of pulmonary fibrosis. To elucidate the role of fibrin deposition and fibrinolysis in the process of pulmonary fibrosis, we studied bleomycin-induced fibrosis and the effect of urokinase on it. Beagle dogs were injected intramuscularly 20 times with bleomycin in doses of 2 and 6 mg/kg body weight every other day. Intravenous urokinase treatment was subsequently performed with 3,000 units daily for 40 days and 9,000 units twice daily for 70 days. Histopathologic examination of the lungs of dogs receiving bleomycin alone revealed fibrosis. The lungs of bleomycin-treated dogs which received urokinase had less severe fibrosis and this was confirmed by morphometry with planimetry and the point counting method. Urokinase treatment also diminished the increase of hydroxyproline content of the lung of bleomycin-treated dogs. Decrease of lung tissue fibrinolytic activity assayed by fibrin plate method in bleomycin-treated dogs was also prevented by urokinase. Intravenous urokinase, 24,000 units per day in divided doses, was administered daily in cancer patients with bleomycin treatment. Incidence of pulmonary fibrosis was decreased by urokinase. These data indicate that fibrin deposition and fibrinolysis may have an important influence on the fibrotic process in the lung.

Topics: Animals; Dogs; Fibrin; Fibrinolysis; Pulmonary Fibrosis; Urokinase-Type Plasminogen Activator

Although pulmonary fibrin deposition and coagulation abnormalities have been observed in acute lung injury in humans, their role in the pathogenesis of pulmonary disorders is unclear. In order to gain further insights into the role of the coagulation in lung injury, we examined the relationship between procoagulant activity in bronchoalveolar lavage (BAL) fluids and the evolution of bleomycin-induced lung injury in marmosets. The BAL procoagulant activity was increased at 1, 2, and 4 wk after bleomycin challenge compared with that in control subjects, and it was capable of shortening the recalcification times of plasmas deficient in factor VII and factor VIII but not in factor X. This profile suggested the presence in BAL of an activator of factor X. Activation of purified human factor X by BAL was demonstrated by measuring the amidolytic activity of the generated factor Xa on its N-benzoyl-L-isoleucyl L-glutamyl-glycyl-L-argenine-p-nitroanilide substrate. Factor X activating activity was increased in BAL at 2 wk after bleomycin challenge. Cleavage of 125I-labeled human factor X by BAL from bleomycin-challenged marmosets yielded a 55,500 Mr product that comigrated with factor Xa, the appearance of which correlated strongly with amidolytic evidence of factor Xa activity. Electron microscopy of the lungs of animals from all groups revealed pulmonary fibrin deposition at 2 wk after bleomycin challenge, at the time of increased BAL procoagulant and factor X activating activity. The BAL procoagulant activity was completely sedimentable by ultracentrifugation and was inhibited by concanavalin A and phospholipase C. Activation of purified factor X by BAL was inhibited by monospecific polyclonal goat and rabbit antibodies to human factor VII as well as antibody to bovine tissue factor, demonstrating that factor X activating activity in BAL was attributable to tissue factor associated with material similar to factors VII or VIIa. We conclude that procoagulant activity in BAL increases after bleomycin challenge in marmosets and is attributable to activation of factor X by tissue factor associated with factors VII or VIIa-like material. Increased BAL procoagulant activity is temporally associated with pulmonary fibrin deposition and pulmonary fibrosis during bleomycin-induced pulmonary injury in the marmoset.

Topics: Animals; Bleomycin; Blood Coagulation Factors; Blood Coagulation Tests; Bronchi; Callitrichinae; Factor VII; Factor VIIa; Factor X; Female; Fibrin; Lung; Male; Pulmonary Alveoli; Pulmonary Fibrosis; Therapeutic Irrigation; Time Factors

Topics: Animals; Fibrin; Fibronectins; Gelatin; Heparin; Histocytochemistry; Immunodiffusion; Lung; Pulmonary Fibrosis; Rats

Fibrin deposition is prominent in the histopathologic features of chronic interstitial lung disease. Human alveolar macrophages can potentially modulate this process because normal macrophages synthesize and express the initial enzymes of both coagulation and fibrinolytic pathways. In the present study, we examined the cell-associated procoagulant activity of macrophages lavaged from patients with sarcoidosis (n = 14) or idiopathic pulmonary fibrosis (n = 13) and compared the enzyme activities with that of a group of normal volunteers (n = 16). Cells from sarcoid patients had a mean (+/- 1 SD) tissue factor activity of 1,491 +/- 2,160 units/5 X 10(5) cells, as compared with a mean of 480 units (range, 140 to 1,000 units) for normal control subjects. The same cells had a mean plasma Factor VII equivalent of 4.7 ng/10(6) cells, as compared with 0.81 ng/10(6) cells (range, 0.2 to 2.0 ng) for the normal control subjects. The enhanced activity correlated with disease activity as judged by radiographic stage: only patients with Stage II or Stage III disease had consistently elevated procoagulant activity. There was no correlation of procoagulant activity with the percentage of lymphocytes in the alveolar fluid. Cells from patients with idiopathic pulmonary fibrosis also had increased tissue factor (mean, 2,980 +/- 2,619 units) but less consistently elevated Factor VII. There was considerable variation in both procoagulant activity and cell differentials between lavage sites in 10 patients in whom 2 separate lobes were studied concurrently. In addition, we examined the plasminogen activator (PA) activities of lavaged cells and concentrated alveolar fluids.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Factor VII; Female; Fibrin; Fibrinolysis; Humans; Inflammation; Macrophages; Male; Middle Aged; Plasminogen Activators; Pulmonary Alveoli; Pulmonary Fibrosis; Sarcoidosis; Thromboplastin

It has been suggested that fibrosis which develops after irradiation is caused by increases in vascular permeability. Plasma proteins leak into irradiated tissue where fibrinogen may be converted into fibrin which is gradually replaced by fibrous tissue. Vascular and fibrotic changes in mouse lung were investigated after X irradiation of the right hemithorax. Blood volume and accumulation of extravascular proteins were measured using indium (111In)-labeled red cells, iodinated (131I) albumin, and iodinated (125I) fibrinogen. Tracers were injected 1-47 weeks after irradiation and lungs were excised 24 or 96 hr later to determine radioactivity. The amount of collagen was estimated by measuring the hydroxyproline content. During the first few months after X rays, lung blood volume decreased to a plateau which depended on radiation dose (10-25 Gy). Small increases in extravascular albumin and fibrinogen occurred at 1-12 weeks after 10-25 Gy. Subsequently, protein returned to normal after 10 Gy, remained elevated after 15 Gy, and increased after 20 and 25 Gy. Hydroxyproline per gram of dry irradiated lung was increased at 18 weeks after 15-25 Gy. Subsequently it showed little change although both total hydroxyproline content and dry weight decreased after 20 and 25 Gy. Support for the hypothesis was that hydroxyproline per gram only increased after X-ray doses which caused marked extravasation of protein. There was no evidence, however, for deposition of 125I-fibrin or for a gradual increase in fibrosis corresponding to the prolonged excess of extravascular protein.

Topics: Albumins; Animals; Blood Proteins; Blood Volume; Capillary Permeability; Collagen; Female; Fibrin; Fibrinogen; Hydroxyproline; Lung; Mice; Mice, Inbred C3H; Organ Size; Pulmonary Fibrosis; Radiation Injuries, Experimental

Patients with acute Legionnaires' disease (LD) pneumonia may have persistent chronic pulmonary changes, as shown by the histologic appearance of specimens of lung from patients who had survived and autopsy specimens from patients who died after a protracted clinical course. Acute pneumonia was not seen in these lungs, and LD organisms could not be identified by the direct fluorescent antibody technique or the Dieterle silver impregnation strain; instead, there was organizing pneumonia with various degrees of interstitial inflammation and fibrosis. The LD pneumonia may fail to resolve, and the lung parenchyma in areas of previous acute inflammation is not restored to normal in some patients.

Topics: Adult; Female; Fibrin; Humans; Inflammation; Legionnaires' Disease; Lung; Male; Middle Aged; Pulmonary Fibrosis

Forty-two patients underwent open-lung biopsy during the early phase of acute respiratory insufficiency. Correlation between the gross appearance of the lung at operation and the microscopic findings was good. Although only fair correlation was found between lung and tracheal cultures, the findings of two positive cultures in the lung only was of utmost importance. Biopsying multiple areas from the same operation showed identical pathology in 86 per cent of cases. The mortality rate of open-lung biopsy was zero; the morbidity rate was 4 per cent. The over-all survival rate of acute respiratory insufficiency (ARI) due to trauma was 39 per cent; that of pneumonia, 11 per cent. In 17 (33 percent) patients specific diagnoses and/or specific therapies were employed as a direct result of the biopsy or the thoracotomy. The incidence and prognostic implications of fibrosis and microthromboembolism are presented and discussed. Open-lung biopsy has been extremely safe and valuable in characterizing and managing ARI.

Topics: Acute Disease; Biopsy; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Humans; Lung; Pulmonary Embolism; Pulmonary Fibrosis; Respiratory Insufficiency

Administration of 0.5 mg bleomycin to mice twice weekly for 4 weeks induced pulmonary fibrosis. The initial site of injury was the intima of pulmonary arteries and veins where endothelial cells became edematous and were separated from the underlying basement membrane by large blebs. These lesions occurred after 2 weeks and were associated with infiltration of perivascular spaces by lymphocytes and plasma cells. Capillary endothelial blebbing and interstitial edema were observed after 4 weeks, when multifocal necrosis of type 1 alveolar epithelial cells was accompanied by fibrinous exudation into the alveoli. The process of repair was characterized by proliferation and metaplasia of type 2 epithelial cells, fibroblastic organization of alveolar fibrin and fibrosis of the interstitium within 8 to 12 weeks. The consistent induction of changes similar to those of diffuse pulmonary fibrosis or fibrosing alveolitis in man suggests that bleomycin-induced injury may provide a suitable model for the investigation of this ill-defined group of diseases.

Topics: Animals; Bleomycin; Capillaries; Disease Models, Animal; Endothelium; Epithelium; Exudates and Transudates; Fibrin; Fibroblasts; Lung; Lymphocytes; Metaplasia; Mice; Microscopy, Electron; Necrosis; Plasma Cells; Pulmonary Alveoli; Pulmonary Artery; Pulmonary Edema; Pulmonary Fibrosis; Pulmonary Veins

Topics: Arthritis, Rheumatoid; Autopsy; Collagen Diseases; Dermatomyositis; Diagnosis, Differential; Fibrin; Granuloma; Histocytochemistry; Humans; Lung; Lupus Erythematosus, Systemic; Polyarteritis Nodosa; Pulmonary Alveoli; Pulmonary Fibrosis; Rheumatic Fever; Scleroderma, Systemic

Topics: Aged; Biopsy; Collagen; Diagnosis, Differential; Fibrin; Humans; Lung; Male; Pulmonary Alveoli; Pulmonary Fibrosis; Radiography; Spondylitis, Ankylosing; Tuberculosis, Pulmonary