Role of HGF in the healthy and injured lung

Abstract

Hepatocyte growth factor (HGF) is a cytokine with pleiotropic functions during wound healing and repair. Its anti-fibrotic effects have been proven in the bleomycin model of lung fibrosis and linked to improved survival and proliferation of epithelial cells and reduction of myofibroblast accumulation. Main goals of this study were to characterize the role of HGF for maintenance of a regular alveolar structure and to investigate the role of HGF in novel animal models of lung fibrosis. We generated transgenic mice with inducible knockout of HGF and its receptor cMet, respectively. In contrast to our expectations, knockout of HGF or lung epithelial cell-specific knockout of cMet for up to 8 weeks in otherwise healthy adult mice did not forward a lung-specific phenotype, especially no lung fibrosis. Both knockout lines breathed and lived normally, showed no impairment of lung function, and forwarded a normal lung morphology and structure. Differential cell counts from BALF indicated no signs of inflammation. Further studies with these mice are underway to examine the role of HGF or cMet knockout in injured animals. With regard to therapeutic interventions, we focused on the non-inflammatory driven mouse model of amiodarone-induced lung fibrosis, recently developed by our group. Application of recombinant HGF is currently studied in this model to answer the question if HGF may be helpful to alleviate alveolar epithelial stress and therefore attenuate the extent of lung fibrosis. Our results indicate that HGF signaling is not required for the maintenance of a regular alveolar structure. Further studies are needed to characterize the role of HGF under disease conditions and to elucidate the underlying protective mechanism.