Pulmonary fibrosis is characterized by a loss of lung epithelial cells, replaced by interstitial myofibroblasts to deposit extracellular matrix (ECM)
proteins. Previous studies demonstrated that
hepatocyte growth factor (HGF) improved lung
fibrosis in murine models, whereas molecular mechanisms whereby HGF improved lung
fibrosis have yet to be fully understood. When MRC-5 human lung fibroblasts were treated with
transforming growth factor-beta1, the cells underwent phenotypic change similar to myofibroblasts and this was associated with up-regulation of c-Met/
HGF receptor expression. For the myofibroblast-like cells, HGF increased activities of
MMP-2/-9, predominant
enzymes for breakdown of
fibronectin (FN). Under such conditions, HGF induced caspase-dependent apoptosis, linked with a decrease in a FN central cell binding (CCB) domain involved in FAK phosphorylation. When
MMI270 (a broad-spectrum
MMP inhibitor) was added together with HGF, decreases in FN-CCB domain expression and FAK phosphorylation by HGF were restored, and these events were associated with an inhibition of HGF-induced apoptosis, suggesting that increased activities of
MMPs underlie the major mechanism of HGF-mediated apoptosis in myofibroblasts.
In bleomycin-treated mice, c-Met expression was found on interstitial myofibroblasts and HGF increased apoptosis in culture of myofibroblasts isolated from
bleomycin-treated murine lungs. Furthermore, administration of recombinant HGF to
bleomycin-treated mice increased lung
MMP activities and enhanced myofibroblast apoptosis, while in vivo
MMI270 injections together with HGF inhibited such
MMP activation, leading to suppressed myofibroblast apoptosis. In conclusion, we identified HGF as a key
ligand to elicit myofibroblast apoptosis and ECM degradation, whereas activation of the HGF/c-Met system in fibrotic lungs may be considered a target to attenuate progression of chronic lung disorders.