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(Circulation. 2005;111:1407-1414.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Amelioration of Pulmonary Emphysema by In Vivo Gene Transfection With Hepatocyte Growth Factor in Rats

Norihisa Shigemura, MD; Yoshiki Sawa, MD, PhD; Shinya Mizuno, PhD; Masamichi Ono, MD; Mitsunori Ohta, MD; Toshikazu Nakamura, PhD; Yasufumi Kaneda, MD, PhD; Hikaru Matsuda, MD, PhD

From the Department of Surgery (N.S., Y.S., M. Ono, M. Ohta, H.M.), Division of Molecular Regenerative Medicine, Course of Advanced Medicine (S.M., T.N.), and Department of Gene Therapy Science (Y.K.), Osaka University Graduate School of Medicine, Osaka, Japan.

Correspondence to Yoshiki Sawa, MD, Department of Surgery, Osaka University Graduate School of Medicine, E1, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail sawa{at}surg1.med.osaka-u.ac.jp

Received June 15, 2004; revision received October 17, 2004; accepted October 25, 2004.

Background— Hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after lung injury. The goal of the present study was to characterize its role in pulmonary emphysema, which may lead to the development of new treatment strategies with HGF.

Methods and Results— HGF mRNA and protein levels in lung tissue and plasma from elastase-induced emphysema rats transiently increased, then declined significantly to below the basal level in a time-dependent manner (P<0.01). Furthermore, changes in HGF were correlated with histologically progressive emphysematous changes and deterioration in pulmonary physiology. Use of the HVJ (hemagglutinating virus of Japan) envelope method resulted in successful transfection of cDNA encoding human HGF, as demonstrated by an efficient expression of HGF in alveolar endothelial and epithelial cells. Transfection of HGF resulted in a more extensive pulmonary vasculature and inhibition of alveolar wall cell apoptosis, and those effects led to improved exercise tolerance and gas exchange (P<0.05), which persisted for more than 1 month.

Conclusions— Decreased HGF expression due to a failure in sustained endogenous production after injury was associated with emphysema-related histopathologic and physiological changes in the present rat model. In addition, induction of HGF expression by a gene-transfection method resulted in improved pulmonary function via inhibition of alveolar cell apoptosis, enhancement of alveolar regeneration, and promotion of angiogenesis.

Key Words: lung • growth substances • gene therapy • hypoxia • angiogenesis

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