Reorganization of alveolar capillaries in pulmonary fibrosis by gene trasfection of Hepatocyte Growth Factor

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Hepatocyte growth factor (HGF), a pluripotent mediator with anti-fibrotic effects, is a candidate gene therapy for idiopathic pulmonary fibrosis for which current therapy is minimally effective. We examined human 11(hHGF) gene transfer by a unique gene delivery system using macroaggregated albumin-polyethylenimine conplex (MM-PEI). which induces lung specific gene expression without causing inflammation. lntravenous administration of MAA-PEI with 1 μg pCAG.hHGF (MAA-PEI+pCAG.hHGF) to C57BL/6 mice induced a level of hHGF expression in the lung equal to 10 μg of pCAG.hHGF alone, prolonged its expression only in the lung, and reduced the hHGF express ion in other organs. In situ RT-PCR revealed hHGF production in endothelial cells, alveolar macrophages, and alveolar epithelial cells, but not in airway epithelial cells. Inflammatory cytokines (TNF-α and IL-6) and collagen synthesis in the lungs after bleomycin injury were statistically decreased by MAA-PEI+pCAG.hHGF injection. Since regeneration of alveolar epithelial cells and capillary endothelial cells by bone marrow-derived stem cells after bleomycin-induced injury was unaffected by HGF, the primary anti-inflammatory and anti-fibrotic mechanism of HGF after lung injury is likely to be the inhibition of apoptosis, as suggested by in vitro experiments. These results indicate that this novel HGF gene transfer system may have promising clinical applications.