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Published ahead of print on August 28, 2003, doi:10.1164/rccm.200212-1514OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 10, November 2003, 1156-1161

A more recent version of this article appeared on November 15, 2003
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Submitted on December 24, 2002
Accepted on August 19, 2003

Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis

Sylvain Marchand-Adam1, Joelle Marchal1, Murielle Cohen2, Paul Soler1, Benedicte Gerard3, Yves Castier4, Guy Leseche4, Dominique Valeyre5, Herve Mal6, Michel Aubier7, Monique Dehoux2, and Bruno Crestani7*

1 Faculte Xavier Bichat, Institute National de la Sante et de la Recherche Medicale, Unit 408, Paris, France, 2 Faculte Xavier Bichat, Institute National de la Sante et de la Recherche Medicale, Unit 408, Paris, France; Hopital Bichat, Laboratoire de Biochimie A, Paris, France, 3 Hopital Bichat, Laboratoire de Biochimie Hormonale et Genetique, Paris, France, 4 Hopital Beaujon, Service de Chirurgie Thoracique et Vasculaire, Clichy, France, 5 Hopital Avicenne, Service de Pneumologie, Bobigny, France, 6 Faculte Xavier Bichat, Institute National de la Sante et de la Recherche Medicale, Unit 408, Paris, France; Hopital Beaujon, Service de Pneumologie, Clichy, France, 7 Faculte Xavier Bichat, Institute National de la Sante et de la Recherche Medicale, Unit 408, Paris, France; Hopital Bichat, Service de Pneumologie, Paris, France

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

Hepatocyte growth factor (HGF) is a growth factor for alveolar epithelial cells that protects from pulmonary fibrosis in different animal models. We compared in vitro HGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n=8) and from controls (n=6). Basal HGF secretion by IPF fibroblasts was decreased by 50% when compared to control fibroblasts (p<0.05). HGF was mainly secreted in the cleaved mature form, both in IPF and control fibroblasts. HGF mRNA levels were reduced in IPF fibroblasts. Prostaglandin E2 secretion by IPF fibroblasts was very low when compared to controls (p<0.05). After the addition of PGE2 (10-6 M) or dibutyryl cyclic AMP (10-3 M), HGF secretion by IPF fibroblasts reached the level of controls. Inhibition of PGE2 synthesis with indomethacin reduced HGF secretion by control fibroblasts but had no effect on IPF fibroblasts. HGF secretion by control fibroblasts was also slightly inhibited by TGFb1 and stimulated by anti-TGFb antibody, whereas both agents had no effect on IPF fibroblasts. Our results demonstrate a defect in HGF production by IPF fibroblasts that seems secondary to a defect in PGE2 secretion.
Key words: Pulmonary alveoli, usual interstitial pneumonia, transforming growth factor beta, indomethacin




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