In vivo hepatic HB-EGF gene transduction inhibits Fas-induced liver injury and induces liver regeneration in mice: a comparative study to HGF.
OBJECTIVE
It is unknown whether heparin-binding EGF-like growth factor (HB-EGF) can be a therapeutic agent, although previous studies suggested that HB-EGF might be a hepatotrophic factor. This study explores the potential of hepatic HB-EGF gene therapy in comparison with HGF.


METHODS
Mice received an intraperitoneal injection of the agonistic anti-Fas antibody 72 h after an intravenous injection of either adenoviral vector (1x10(11) particles) expressing human HB-EGF (Ad.HB-EGF), human HGF (Ad.HGF) or no gene (Ad.dE1.3), and were sacrificed 24 or 36 h later to assess liver injury and regeneration.


RESULTS
Exogenous HB-EGF was predominantly localized on the membrane, suggesting the initial synthesis of proHB-EGF in hepatocytes. The control Ad.dE1.3-treated mice represented remarkable increases in serum ALT and AST levels and histopathologically severe liver injuries with numerous apoptosis, but a limited number of mitogenic hepatocytes. In contrast, the liver injuries and apoptotic changes were significantly inhibited, but the mitogenic hepatocytes remarkably increased, in both the Ad.HB-EGF- and Ad.HGF-treated mice. More mitogenic hepatocytes and milder injuries were observed in the Ad.HB-EGF-treated mice.


CONCLUSIONS
HB-EGF has more potent protective and mitogenic effects for hepatocytes than HGF, at least for the present conditions. In vivo hepatic HB-EGF gene transduction is therapeutic for Fas-induced liver injury.
Khai
Ngin Cin
NC
Department of Gene Therapy and Regenerative Medicine, Gifu University School of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Takahashi
Tomoyuki
T
Ushikoshi
Hiroaki
H
Nagano
Satoshi
S
Yuge
Kentaro
K
Esaki
Masayasu
M
Kawai
Takao
T
Goto
Kazuko
K
Murofushi
Yoshiteru
Y
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
Kosai
Ken-ichiro
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002462:Cell Membrane / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000032:analysis / Q000235:genetics*; D015316:Genetic Therapy; D066257:Heparin-binding EGF-like Growth Factor; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000201:enzymology; D008107:Liver Diseases / Q000276:immunology / Q000628:therapy*; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic; D019014:fas Receptor / Q000187:drug effects
D000906:Antibodies; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D019014:fas Receptor; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor