Hepatocyte growth factor (HGF) is a humoral mediator of epithelial-mesenchymal interactions, acting on a variety of epithelial cells as mitogen, motogen, and morphogen. Exogenous HGF acts as a hepatotrophic factor and a renotrophic factor during experimental injury. To investigate whether HGF has a pulmotrophic function, human recombinant HGF was administered to C57BL/6 mice with severe lung injury by bleomycin (BLM). Low dose simultaneous and continuous administration of HGF (50 μ g/mouse/7 d) with BLM (100 mg/mouse/7 d) repressed fibrotic morphological changes at 2 and 4 wk. Ashcroft score showed a significant difference in lung fibrosis with and without HGF at 4 wk (3.7 ± 0.4 versus 4.9 ± 0.3, p < 0.05). Furthermore, either simultaneous or delayed administration of high dose HGF (280 μ g/mouse/14 d) equally repressed fibrotic changes by BLM when examined at 4 wk (Ashcroft score: 2.6 ± 0.4 and 2.4 ± 0.2 versus 4.1 ± 0.2, p < 0.01). Hydroxyproline content in the lungs was significantly lower in mice with either simultaneous or delayed administration of high dose HGF as compared to those administered BLM alone (121.8 ± 8.1% and 113.2 ± 6.2% versus 162.7 ± 4.6%, p < 0.001). These findings indicate that exogenous HGF acts as a pulmotrophic factor in vivo and prevents the progression of BLM-induced lung injury when administered in either a simultaneous or delayed fashion. HGF may be a potent candidate to prevent or treat lung fibrosis.