Involvement of hepatocyte growth factor (HGF) in lung morphogenesis and regeneration has been established by in vitro and in vivo experiments in animals. In the present study, the protective activity of HGF against tumor necrosis factor (TNF)-alpha or hydrogen peroxide (H2O2)-induced damage of pulmonary epithelial cells was examined using the human small airway epithelial cell line (SAEC). Western blot analysis revealed that the receptor for HGF (c-Met) was highly expressed on the surface of SAEC and its downstream signal transduction pathway was functional. The SAEC was induced into apoptosis by the treatment with TNF-alpha or H2O2 in a dose-dependant manner, but was significantly rescued from apoptosis in the presence of HGF. The HGF effect was evident when added not only at the same time but also within several hours after treatment. This protective activity of HGF against the TNF-alpha- or H2O2-induced apoptosis was mediated, at least in part, by up-regulating the nuclear factor kappaB activity and an increase in the ratio of apoptosis-suppressing to apoptosis-inducing proteins. These results suggest that administration of HGF might exhibit a potent function in vivo for protection and improvement of acute and chronic lung injuries induced by inflammation and/or oxidative stress.