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Published ahead of print on March 30, 2006, doi:10.1164/rccm.200507-1074OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 1, July 2006, 58-66

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Submitted on July 12, 2005
Accepted on March 30, 2006

Defect of Pro-Hepatocyte Growth Factor Activation by Fibroblasts in Idiopathic Pulmonary Fibrosis

Sylvain Marchand-Adam1, Aurelie Fabre2, Arnaud Andre Mailleux3, Joelle Marchal2, Christophe Quesnel2, Hiroaki Kataoka4, Michel Aubier1, Monique Dehoux5, Paul Soler2, and Bruno Crestani1*

1 INSERM, Unit 700, Faculte Xavier Bichat, Universite Paris 7, Denis Diderot, Paris, France; APHP, Service de Pneumologie, Hopital Bichat, Paris, France, 2 INSERM, Unit 700, Faculte Xavier Bichat, Universite Paris 7, Denis Diderot, Paris, France, 3 Cell Biology Department, Harvard Medical School, Boston, MA, USA, 4 Faculty of Medicine, University of Miyazaki, Japan, 5 INSERM, Unit 700, Faculte Xavier Bichat, Universite Paris 7, Denis Diderot, Paris, France; Laboratoire de Biochimie A, Hopital Bichat, Paris, France

* To whom correspondence should be addressed. E-mail: bruno.crestani{at}bch.aphp.fr.

Rationale and objectives: Hepatocyte growth factor (HGF) protects against lung fibrosis in several animal models. Pro-HGF activation to HGF is subjected to a regulation by its activator (HGFA), a serine protease, and HGFA specific inhibitors (HAI-1 and HAI-2). Our hypothesis was that fibroblasts from 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 controls and from IPF patients 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 PGE2 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 HAI-1 and HAI-2. Pro-HGF activation by IPF fibroblasts was reduced compared to controls. In IPF fibroblasts, HGFA expression was lower and HAI-1 and HAI-2 expression was higher compared to control fibroblasts. PGE2 stimulated pro-HGF activation, through an increased expression of HGFA and a decreased expression of its inhibitor HAI-2. In contrast, TGF-{beta}1 reduced the ability of lung fibroblasts to activate pro-HGF through a decreased expression of HGFA and an 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, while PGE2 is able to partially correct this defect.
Key words: human,lung, serine protease, usual interstitial pneumonia, prostaglandin E2




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