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Published ahead of print on May 15, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2008-0305OC
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Submitted on August 5, 2008
Accepted on May 15, 2009

Imbalance in the pro-HGF Activation System in Bleomycin-induced Lung Fibrosis in Mice

Sophie Phin1, Sylvain Marchand-Adam2, Aurelie Fabre3, Joelle Marchal-Somme1, Claudie Bantsimba-Malanda1, Hiroaki Kataoka4, Paul Soler1, and Bruno Crestani5*

1 Unit 700, Faculté Xavier-Bichat, Inserm, Paris, France, 2 Unit 700, Faculté Xavier-Bichat, Inserm, Paris, France; Université Paris 7 denis Diderot, Paris, France; Unit 618, Facutlé Médecine, Université Francois Rabelais, Inserm, Tours, France, 3 Unit 700, Faculté Xavier-Bichat, Inserm, Paris, France; Université Paris 7 denis Diderot, Paris, France, 4 Miyazaki Medical College, Miyazaki, Japan, 5 Unit 700, Faculté Xavier-Bichat, Inserm, Paris, France; Université Paris 7 denis Diderot, Paris, France; Hopital Bichat, Service de Pneumologie A, APHP, Paris, France

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

Hepatocyte growth factor (HGF) is a growth factor for alveolar epithelial cells. Activation of Pro-HGF to HGF is regulated by the HGF activator (HGFA), a serine protease, and a specific inhibitor (HGFA inhibitor-1, HAI-1). An imbalance in the HGFA/HAI-1 system might contribute to lung fibrosis. ProHGF activation capacity from BAL fluid was evaluated 3, 7 and 14 days after the intratracheal bleomycin injection (Bleo) in mice with or without thrombin. BAL fluid from naive mice was used as control. HGFA and HAI-1 mRNA were evaluated by QPCR in the whole lung or by Western Blot in BAL fluid. BAL fluid from control mice and Bleo mice activated proHGF in vitro at a similar degree. Thrombin accelerated proHGF activation by Bleo BAL on day 3 and day 7, but not on day 14, or in control BAL. Incubation of proHGF with BAL from Bleo day 3 and day 7 mice increased phosphorylation of HGFR on A549 cells. Thrombin-induced proHGF activation was inhibited by an anti-HGFA antibody and accelerated by an anti-HAI-1 antibody. Active HGFA was not detected in control BAL and was strongly induced in Bleo BAL. HGFA concentrations were higher on day 3 and day 7 than on day 14. HAI-1 was detected at low levels in control BAL and increased strongly by day 3 with stable concentrations until day 14. By demonstrating an imbalance between HGFA and HAI-1 expression in BAL fluid, our results highlight a defective thrombin-dependent proHGF activation system at the fibrotic phase of bleomycin-induced pulmonary fibrosis.
Key words: serin protease • alveolar repair • idiopathic lung fibrosis • broncho-alveolar lavage • mouse






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