Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis.
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.
Watanabe
Masaki
M
Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan.
Ebina
Masahito
M
Orson
Frank M
FM
Nakamura
Akira
A
Kubota
Kazuo
K
Koinuma
Daizo
D
Akiyama
Ken-ichi
K
Maemondo
Makoto
M
Okouchi
Shinya
S
Tahara
Minoru
M
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Nukiwa
Toshihiro
T
D000418:Albumins; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells; D016207:Cytokines / Q000097:blood; D015316:Genetic Therapy; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011094:Polyethyleneimine; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000628:therapy*; D013234:Stem Cells; D013667:Technetium
D000418:Albumins; D016207:Cytokines; D017228:Hepatocyte Growth Factor; D013667:Technetium; D011094:Polyethyleneimine