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

Inserm Unit 700, Institut National de la Santé et de la Recherche Medicale, Faculté Xavier Bichat; Université Paris 7, Denis Diderot; Service de Pneumologie, Assistance Publique–Hôpitaux de Paris; Laboratoire de Biochimie A, Hôpital Bichat, Paris, France; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; and Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

Correspondence and requests for reprints should be addressed to Bruno Crestani, M.D., Service de Pneumologie, Hôpital Bichat, 16 rue Henri Huchard, 75877 Paris, Cedex 18, France. 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 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-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 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. PGE₂ stimulated pro-HGF activation through increased expression of HGFA and decreased expression of its inhibitor HAI-2. In contrast, TGF-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 PGE₂ is able to partially correct this defect.

Key Words: human • lung • prostaglandin E₂ • serine protease • usual interstitial pneumonia

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