Amelioration of pulmonary emphysema by in vivo gene transfection with hepatocyte growth factor in rats.
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.


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.
Shigemura
Norihisa
N
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Sawa
Yoshiki
Y
Mizuno
Shinya
S
Ono
Masamichi
M
Ohta
Mitsunori
M
Nakamura
Toshikazu
T
Kaneda
Yasufumi
Y
Matsuda
Hikaru
H
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D004195:Disease Models, Animal; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D018919:Neovascularization, Physiologic; D010196:Pancreatic Elastase / Q000633:toxicity; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics; D011652:Pulmonary Circulation; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000235:genetics; D014161:Transduction, Genetic
D018076:DNA, Complementary; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D010196:Pancreatic Elastase