1. ¹Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan
2. ²Department of Veterans Affairs and Department of Internal Medicine, Department of Immunology, and Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
3. ³Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan
4. ⁴Department of Radiology, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan
5. ⁵Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan

Correspondence: Masahito Ebina, Fax: +81 22 717 8549. E-mail: ebinam@idac.tohoku.ac.jp.

Received 9 September 2004; Accepted 26 February 2005.

Abstract

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 g 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 g of hHGF-expression plasmids alone. The exogenous source of hHGF gene expression increased the endogenous mouse HGF in the lungs and significantly decreased TNF-, 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.