We examined therapeutic gene transfer of human hepatocyte growth factor (hHGF) to alveolar septa in mouse bleomycin-induced lung fibrosis using macroaggregated albumin-polyethylenimine complex (MAA-PEI). Intravenous administration of MAA-PEI along with 1 microg pCAG.hHGF to C57BL/6 mice increased the uptake of plasmids into alveolar capillary endothelial cells and epithelial cells, prolonged hHGF expression in the lung, and induced a level of hHGF expression equal to that seen with 10 microg of hHGF-expression plasmids alone. The exogenous source of hHGF gene expression increased the endogenous mouse HGF in the lungs and significantly decreased TNF-alpha, IL-6, and collagen synthesis after bleomycin injury. Because GFP-labeled bone marrow-derived stem cells after bleomycin injury were reduced in number by HGF, the primary mechanism of HGF is likely to be the prevention of apoptosis, as has been suggested by in vitro experiments. This novel HGF gene transfer method to alveolar septa with nonstimulatory MAA-PEI conjugates may have promising clinical applications.