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Am J Respir Crit Care Med. 2006 Jul 1;174(1):58-66. Epub 2006 Mar 30.

Defect of pro-hepatocyte growth factor activation by fibroblasts in idiopathic pulmonary fibrosis.

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  • 1Inserm Unit 700, Institut National de la Santé et de la Recherche Medicale, Faculté Xavier Bichat, Paris, France.

Abstract

RATIONALE AND OBJECTIVES:

Hepatocyte growth factor (HGF) protects against lung fibrosis in several animal models. Pro-HGF activation to HGF is subjected to regulation by its activator (HGFA), a serine protease, and HGFA-specific inhibitors (HAI-1 and HAI-2). Our hypothesis was that fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) had an altered capacity to activate pro-HGF in vitro compared with control fibroblasts.

METHODS:

We measured the kinetics of pro-HGF activation in human lung fibroblasts from control subjects and from patients with IPF by Western blot. HGFA, HAI-1, and HAI-2 expression was evaluated by immunohistochemistry, RNA protection assay, and Western blot. We evaluated the effect of TGF-beta(1) and PGE(2) on pro-HGF activation and HGFA, HAI-1, and HAI-2 expression.

MAIN RESULTS:

Lung fibroblasts activated pro-HGF in vitro. Pro-HGF activation was inhibited by serine protease inhibitors, by an anti-HGFA antibody, as well as by HAI-1 and HAI-2. Pro-HGF activation by IPF fibroblasts was reduced compared with control fibroblasts. In IPF fibroblasts, HGFA expression was lower and HAI-1 and HAI-2 expression was higher compared with control fibroblasts. PGE(2) stimulated pro-HGF activation through increased expression of HGFA and decreased expression of its inhibitor HAI-2. In contrast, TGF-beta(1) reduced the ability of lung fibroblasts to activate pro-HGF through decreased expression of HGFA and increased expression of its inhibitors.

CONCLUSIONS:

IPF fibroblasts have a low capacity to activate pro-HGF in vitro via a low level of HGFA expression and high levels of HAI-1 and HAI-2 expression, and PGE(2) is able to partially correct this defect.

PMID:
16574935
[PubMed - indexed for MEDLINE]
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