Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis

Kotani, Izumi; Sato, Atsuhiko; Hayakawa, Hiroshi; Urano, Tetsumei; Takada, Yumiko; Takada, Akikazu

doi:10.1016/0049-3848(95)00025-9

Cited by 176 publications

(137 citation statements)

References 24 publications

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“…Supporting, but not providing direct evidence for a role for coagulation cascade proteins in these diseases, several studies have shown that there is also increased procoagulant activity in the lungs and bronchoalveolar lavage fluid from patients with these conditions [3,4]. 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].…”

Section: Involvement Of Coagulation Cascade Proteins In Interstitial supporting

confidence: 66%

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: 66%

From clot to collagen: coagulation peptides in interstitial lung disease

Dabbagh¹,

Chambers²,

Guy³

1998

Eur Respir J

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“…21 During IPF, increased levels of inhibitors, in particular PAI-1, suppress this fibrinolytic activity. 2 Our data show, for the first time, that there is also an abnormal high level of PN-1 in BALF from patients with IPF. PN-1 has been previously shown to limit fibrinolysis within a blood clot via its ability to inhibit plasminergic enzymes.…”

Section: Discussionmentioning

confidence: 78%

“…High levels of PAI-1 have been observed in IPF and are associated with poor clinical outcomes. 2,19 We demonstrated in this study that PN-1, another serpin, was also abnormally highly expressed in the fibrotic lung tissue and detected in BALF from patients with IPF. Until now, no data were available concerning the role of PN-1 in the pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 88%

Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

François

Vénisse

Marchal-Sommé

et al. 2014

Laboratory Investigation

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Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse lung disease characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 (PN-1) is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, thrombin and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during IPF. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with IPF. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-b, a major pro-fibrotic cytokine involved in IPF. Another serpin, plasminogen activator inhibitor-1 (PAI-1) is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from IPF and stimulated fibroblasts were shown to inhibit efficiently thrombin activity, indicating that both serpins should exhibit complementary roles in IPF pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased fibronectin expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased fibronectin expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on fibronectin expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of IPF by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in IPF and could therefore give rise to new therapeutic approaches.

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“…Several of these enzymes, including metalloproteases, collagenases, gelatinases, plasmin, and plasminogen activators (PA), can directly catalyze the degradation of extracellular matrix (ECM) components (1,2,5). Thus, an unbalance between these proteases and their specific inhibitors may promote ECM deposition.…”

mentioning

confidence: 99%

“…An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis (1)(2)(3)(4)(5)(6). Several of these enzymes, including metalloproteases, collagenases, gelatinases, plasmin, and plasminogen activators (PA), can directly catalyze the degradation of extracellular matrix (ECM) components (1,2,5).…”

mentioning

confidence: 99%

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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Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis

Cited by 176 publications

References 24 publications

From clot to collagen: coagulation peptides in interstitial lung disease

From clot to collagen: coagulation peptides in interstitial lung disease

Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

Protease-Activated Receptor-2 Expression in IgA Nephropathy

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