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

Am J Respir Crit Care Med. 2006 Jul 1;174(1):58-66. doi: 10.1164/rccm.200507-1074OC. Epub 2006 Mar 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Cell Culture Techniques
  • Dinoprostone / physiology
  • Female
  • Fibroblasts / physiology*
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Middle Aged
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Proteinase Inhibitory Proteins, Secretory / genetics
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • RNA, Messenger / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Transforming Growth Factor beta1 / physiology


  • Membrane Glycoproteins
  • Protein Precursors
  • Proteinase Inhibitory Proteins, Secretory
  • RNA, Messenger
  • SPINT1 protein, human
  • SPINT2 protein, human
  • Transforming Growth Factor beta1
  • pro-hepatocyte growth factor
  • Hepatocyte Growth Factor
  • HGF activator
  • Serine Endopeptidases
  • Dinoprostone