title: HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis.
abstract: 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.
authors.affiliation: Division of Molecular Regenerative Medicine, Department of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Mizuno
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Ming-Yue
authors.initials: MY
authors.lastname: Li
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001761:Bleomycin; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005353:Fibronectins / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008168:Lung / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000201:enzymology / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011719:Pyrazines / Q000494:pharmacology; D011994:Recombinant Proteins; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000199:Actins; C097658:CGS 27023A; D004791:Enzyme Inhibitors; D005353:Fibronectins; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D013449:Sulfonamides; D001761:Bleomycin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9