Role of thrombin in pulmonary fibrosis

Hernández-Rodríguez, Norma A.; Cambrey, Alison D.; Chambers, Rachel C.; Gray, Andrew; McAnulty, Robin J.; Guy, Laurent; Harrison, N K; Southcott, A M; duBois, Roland M.; Black, Carol M.; Scully, M F

doi:10.1016/s0140-6736(95)91744-6

Cited by 147 publications

(97 citation statements)

References 7 publications

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“…Similar findings have been reported for patients with chronic interstitial lung disease [5], including patients with idiopathic pulmonary fibrosis (IPF), as well as with pulmonary fibrosis associated with systemic sclerosis (SSc) [6,7]. Consistent with these findings, we and others have shown that thrombin levels are increased in bronchoalveolar lavage (BAL) fluid obtained from patients with pulmonary fibrosis associated with SSc [8,9], and that thrombin is a major fibroblast mitogen present in these fluids [9]. Similar findings have also been reported for animal models of fibrosis.…”

Section: Involvement Of Coagulation Cascade Proteins In Interstitial supporting

confidence: 87%

From clot to collagen: coagulation peptides in interstitial lung disease

Dabbagh¹,

Chambers²,

Guy³

1998

Eur Respir J

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Section: Involvement Of Coagulation Cascade Proteins In Interstitial supporting

confidence: 87%

From clot to collagen: coagulation peptides in interstitial lung disease

Dabbagh¹,

Chambers²,

Guy³

1998

Eur Respir J

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“…Coagulation cascade activation is a prominent feature of both acute and chronic inflammatory processes. Several reports support the hypothesis of a key role for coagulation factors in the pathogenesis of tissue fibrosis, particularly within the kidney (8,(27)(28)(29)(30). Interestingly, earlier works suggested that FXa, the enzymatically active constituent of the prothrombinase complex, triggers complex pathways involved in the regulation of cellular growth (31,32).…”

mentioning

confidence: 87%

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-β, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-β expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN. E-mail: g.grandaliano@nephro.uniba.it

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“…Activation of the coagulation cascade is one of the earliest events following tissue injury and is also a common feature of a number of acute and chronic pathological conditions associated with proliferative responses and excess deposition of matrix proteins, including atherosclerosis (8), restenosis after vascular injury (6,7), glomerulonephritis (10), and pulmonary fibrosis (9). These conditions are also associated with increased CTGF expression.…”

Section: Thrombin Exerts Its Stimulatory Effects On Ctgf Expression Vmentioning

confidence: 99%

“…Thrombin also promotes the production and secretion of extracellular matrix proteins (2,3) and influences connective tissue remodeling processes (4). There is increasing in vivo evidence that the pro-inflammatory and pro-fibrotic effects of thrombin play an important role in both normal tissue and vascular repair (5), as well as in a number of pathological conditions associated with acute or persistent activation of the coagulation cascade, including restenosis and neointima formation following vascular injury (6,7), atherosclerosis (8), pulmonary fibrosis (9), and glomerulonephritis (10).…”

mentioning

confidence: 99%

Thrombin Is a Potent Inducer of Connective Tissue Growth Factor Production via Proteolytic Activation of Protease-activated Receptor-1

Chambers

Leoni

Blanc‐Brude

et al. 2000

Journal of Biological Chemistry

227

170

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The coagulation protease thrombin plays a critical role in hemostasis and exerts pro-inflammatory and profibrotic effects via proteolytic activation of the major thrombin receptor, protease-activated receptor-1 (PAR-1). Connective tissue growth factor (CTGF) is a novel fibroblast mitogen and also promotes extracellular matrix protein production. It is selectively induced by transforming growth factor ␤ (TGF-␤) and is thought to be the autocrine agent responsible for mediating its pro-fibrotic effects. CTGF is up-regulated during tissue repair and in fibrotic conditions associated with activation of the coagulation cascade. We therefore hypothesized that coagulation proteases promote the production of CTGF by cells at sites of tissue injury. To begin to address this hypothesis, we assessed the effect of coagulation proteases on fibroblast CTGF expression in vitro, and we show that thrombin, at physiological concentrations, up-regulated CTGF mRNA levels 5-fold relative to base line (p < 0.01) in fetal fibroblasts and 7-fold in primary adult fibroblasts (p < 0.01). These effects were cycloheximide-insensitive and were not blocked with a pan-specific TGF-␤-neutralizing antibody. They were further paralleled by a concomitant increase in CTGF protein production and could be mimicked with selective PAR-1 agonists. In addition, fibroblasts derived from PAR-1 knockout mice were unresponsive to thrombin but responded normally to TGF-␤ 1 . Finally, factor Xa, which is responsible for activating prothrombin during blood coagulation, exerted similar stimulatory effects. We propose that coagulation proteases and PAR-1 may play a role in promoting connective tissue formation during normal tissue repair and the development of fibrosis by up-regulating fibroblast CTGF expression.

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Role of thrombin in pulmonary fibrosis

Cited by 147 publications

References 7 publications

From clot to collagen: coagulation peptides in interstitial lung disease

From clot to collagen: coagulation peptides in interstitial lung disease

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Thrombin Is a Potent Inducer of Connective Tissue Growth Factor Production via Proteolytic Activation of Protease-activated Receptor-1

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