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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dramatic activation of the coagulation cascade has been extensively documented for pulmonary fibrosis associated with acute and chronic lung injury. In addition to its role in hemostasis, thrombin exerts profibrotic effects via activation of the major thrombin receptor, protease-activated receptor-1. In this study, we examined the effect of the direct thrombin inhibitor, UK-156406 on fibroblast responses in vitro and on bleomycin-induced pulmonary fibrosis in rats. UK-156406 significantly inhibited thrombin-induced fibroblast proliferation, procollagen production, and connective tissue growth factor (CTGF) mRNA levels when used at equimolar concentration to the protease. Thrombin levels in bronchoalveolar lavage fluid and expression of thrombin and protease-activated receptor-1 in lung tissue were increased after intratracheal instillation of bleomycin. The characteristic doubling in lung collagen in bleomycin-treated animals (38.4 +/- 2.0 mg versus 17.1 +/- 1.4 mg, P < 0.01) was preceded by significant elevations in alpha1(I) procollagen and CTGF mRNA levels (3.0 +/- 0.4-fold and 6.3 +/- 0.4-fold respectively, (P < 0.01), and total inflammatory cell number. UK-156406, administered at an anticoagulant dose, attenuated lung collagen accumulation in response to bleomycin by 35 +/- 12% (P < 0.05), inhibited alpha1(I) procollagen and CTGF mRNA levels by 50% and 35%, respectively (P < 0.05), but had no effect on inflammatory cell recruitment. This is the first report showing that direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.
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PMID:Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis. 1158 66

Pulmonary fibrosis is the end stage of a heterogeneous group of disorders and is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium. There is increasing evidence from a number of studies that activation of the coagulation cascade, with the resultant generation of coagulation proteases, plays a central role in fibrotic lung disease that is associated with acute and chronic lung injury. Consistent with this finding, levels of thrombin are increased in bronchoalveolar lavage fluid from patients and in animal models of this disorder. In addition to its classical role in blood coagulation, thrombin exerts a number of proinflammatory and profibrotic cellular effects in vitro that are critically important in tissue repair processes. These cellular effects are predominantly mediated via proteolytic activation of the major thrombin receptor protease-activated receptor-1 (PAR-1). This has led us to hypothesize that the procoagulant and the downstream cellular effects of thrombin, which are initiated following receptor activation, may be important in promoting tissue fibrosis in vivo. To examine this hypothesis, we assessed the effect of a direct thrombin inhibitor in bleomycin-induced pulmonary fibrosis in rats. Immunohistochemical studies showed that expression of thrombin and PAR-1 in lung tissue increased dramatically after intratracheal instillation of bleomycin, compared with saline-treated animals. After bleomycin instillation, there was a doubling in the amount of lung collagen after 14 days, which was preceded by elevations in alpha(1)(I) procollagen and connective tissue growth factor (CTGF) mRNA levels. However, when bleomycin-treated animals concurrently received a continuous infusion of a direct thrombin inhibitor at an anticoagulant dose, lung collagen accumulation in response to bleomycin was attenuated by up to 40%. Furthermore, alpha(1)(I) procollagen and CTGF mRNA levels were also significantly reduced in these animals. These findings confirm that thrombin is a key mediator in the pathogenesis of this condition and suggest that the cellular effects of thrombin may be critically important in promoting lung collagen accumulation in this experimental model of pulmonary fibrosis. Targeting the profibrotic effects of coagulation proteases warrants further evaluation as a potential therapeutic strategy for fibrotic lung disease.
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PMID:Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. 1202 53

Chronic lung disease of prematurity (CLD) is a common consequence of neonatal respiratory distress syndrome (RDS) and is characterized by pulmonary fibrosis. Increased thrombin activity in the alveolar compartment is associated with pulmonary fibrosis in adults and animals, and contributes to bronchoalveolar lavage (BAL) fluid mitogenicity for fibroblasts. We hypothesized that BAL fluid from infants who develop CLD contains increased mitogenic activity for lung fibroblasts compared to BAL fluid from resolving RDS, and that increased thrombin levels contribute to this activity. Sequential BAL (postnatal days 2-14) was obtained from 37 premature infants who were ventilated for RDS. Twenty-six infants developed CLD, whereas 11 resolved. BAL fluid mitogenic activity was determined in a proliferation assay, using human fetal lung fibroblasts. The contribution of thrombin to mitogenic activity was determined using the thrombin inhibitor PPACK. Furthermore, thrombin levels in BAL fluid were measured using a specific substrate to detect thrombin activity and by measuring thrombin-antithrombin III complex (TATIII). BAL fluid mitogenic activity was comparable between CLD and RDS (CLD, 33% proliferation on day 2 to 41% on day 14; RDS, 21% on day 2 to 54% on day 7). Thrombin inactivation by PPACK completely inhibited mitogenic activity in BAL samples obtained on days 2 and 4 (CLD, P < 0.001 on days 2 and 4; RDS, P < 0.05 on day 4). From day 7 onwards, inhibition of thrombin only partly reduced (P < 0.05) CLD BAL fluid mitogenic activity, indicating that other mitogenic factors contribute as well. Surprisingly, thrombin activity and TATIII were decreased in BAL fluid from CLD compared with RDS patients on days 2 and 4. In conclusion, our study shows that BAL fluid from infants with and without CLD development is equally mitogenic for lung fibroblasts, and that thrombin is a major mitogen in these samples. This suggests that fibroproliferation may occur early in the lungs from infants with both CLD and RDS, and that thrombin contributes to this.
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PMID:Thrombin contributes to bronchoalveolar lavage fluid mitogenicity in lung disease of the premature infant. 1246 37

Coagulation and fibrinolytic system deregulation has been implicated in the development of idiopathic pulmonary fibrosis, a devastating form of interstitial lung disease. We used intratracheal instillation of bleomycin to induce pulmonary fibrosis in mice and analyzed the role of serine protease inhibitor E2 (serpinE2)/protease nexin-1 (PN-1), a tissue serpin that exhibits anticoagulant and antifibrinolytic properties. PN-1 deficiency was associated, after bleomycin challenge, with a significant increase in mortality, as well as a marked increase in active thrombin in bronchoalveolar lavage fluids, an overexpression of extracellular matrix proteins, and an accumulation of inflammatory cells in the lungs. Bone marrow transplantation experiments showed that protective PN-1 was derived from hematopoietic cell compartment. A pharmacological strategy using the direct thrombin inhibitor argatroban reversed the deleterious effects of PN-1 deficiency. Concomitant deficiency of the thrombin receptor protease-activated receptor 4 (PAR4) abolished the deleterious effects of PN-1 deficiency in hematopoietic cells. These data demonstrate that prevention of thrombin signaling by PN-1 constitutes an important endogenous mechanism of protection against lung fibrosis and associated mortality. Our findings suggest that appropriate doses of thrombin inhibitors or PAR4 antagonists may provide benefit against progressive lung fibrosis with evidence of deregulated thrombin activity.
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PMID:Hematopoietic protease nexin-1 protects against lung injury by preventing thrombin signaling in mice. 3025 3