Effect of Hepatocyte Growth Factor on Lung Injury and Development of Clinical Application

Abstract

Hepatocyte growth factor (HGF) is a humoral mediator of epithelial-mesenchymal interactions, acting on a variety of epithelial cells. In our previous studies, higher HGF levels were detected in the BAL fluid of patients with pulmonary fibrosis, 1 Sakai T Satoh K Matsushina K et al. Hepatocyte growth factor in bronchoalveolar lavage fluids and cells in patients with inflammatory chest diseases of the lower respiratory tract: detection by RIA and in situ hybridization. Am J Respir Cell Mol Biol. 1997; 16: 388-397 Crossref PubMed Scopus (52) Google Scholar and HGF could prevent the progression of bleomycin-induced lung fibrosis in mice using human recombinant HGF. 2 Yaekashiwa M Nakayama S Ohnuma K et al. Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin: a morphologic study. Am J Respir Crit Care Med. 1997; 156: 1937-1944 Crossref PubMed Scopus (198) Google Scholar To step up the clinical application of HGF for respiratory diseases, we examined the adenoviral-mediated HGF treatment. While the intratracheal administration of adenoviral vector expressing rat HGF (AdCAG.HGF) yielded high transient HGF expression (312.5 ng/g lung tissue, day 3), adenovirus caused neutrophil alveolitis. In spite of indirect intraperitoneal administration of AdCAG.HGF (6 × 108 pfu) to C57BL/6 mice with bleomycin-induced lung injury, reduced hydroxyproline content (128 ± 5%; n = 5, day 28) resulted in AdCAG.HGF-treated mice, compared with mice treated with adenovirus without complementary DNA insertion (177 ± 9%, p < 0.005). Furthermore, the alveolar apoptotic cells in bleomycin-induced lung injury determined by deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling stain was also reduced by the intraperitoneal administration of AdCAG.HGF (35 ± 4% vs 13 ± 1%; p < 0.05). These results indicate the potential therapeutic effect of HGF for lung injury and fibrosis, and thus await the development of the clinical administration.