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


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.
Marchand-Adam
Sylvain
S
Inserm Unit 700, Institut National de la Santé et de la Recherche Medicale, Faculté Xavier Bichat, Paris, France.
Fabre
Aurélie
A
Mailleux
Arnaud André
AA
Marchal
Joelle
J
Quesnel
Christophe
C
Kataoka
Hiroaki
H
Aubier
Michel
M
Dehoux
Monique
M
Soler
Paul
P
Crestani
Bruno
B
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D015232:Dinoprostone / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology
D008562:Membrane Glycoproteins; D011498:Protein Precursors; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; C109149:SPINT1 protein, human; C109148:SPINT2 protein, human; D053773:Transforming Growth Factor beta1; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; C081092:HGF activator; D012697:Serine Endopeptidases; D015232:Dinoprostone