Insulin-like growth factor and epidermal growth factor treatment: new approaches to protecting steatotic livers against ischemia-reperfusion injury.
Hepatic steatosis is a major risk factor in ischemia-reperfusion (I/R). IGF-binding proteins (IGFBPs) modulate IGF-I action by transporting circulating IGF-I to its sites of action. Epidermal growth factor (EGF) stimulates IGF-I synthesis in vitro. We examined the effect of IGF-I and EGF treatment, separately or in combination, on the vulnerability of steatotic livers to I/R. Our results indicated that I/R impaired IGF-I synthesis only in steatotic livers. Only when a high dose of IGF-I (400 microg/kg) was given to obese animals did they show high circulating IGF-I:IGFBP levels, increased hepatic IGF-I levels, and protection against damage. In lean animals, a dose of 100 microg/kg IGF-I protected nonsteatotic livers. Our results indicated that the combined administration of IGF-I and EGF resulted in hepatic injury parameters in both liver types similar to that obtained by IGF-I and EGF separately. IGF-I increased egf expression in both liver types. The beneficial role of EGF on hepatic I/R injury may be attributable to p38 inhibition in nonsteatotic livers and to PPAR gamma overexpression in steatotic livers. In conclusion, IGF-I and EGF may constitute new pharmacological strategies to reduce the inherent susceptibility of steatotic livers to I/R injury.
Casillas-Ramírez
Araní
A
Unitat de Transplantament de Fetge i Viabilitat de l'Empelt, Institut d' Investigaciones Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Zaouali
Amine
A
Padrissa-Altés
Susagna
S
Ben Mosbah
Ismail
I
Pertosa
Anna
A
Alfany-Fernández
Izabel
I
Bintanel-Morcillo
Maria
M
Xaus
Carme
C
Rimola
Antoni
A
Rodés
Juan
J
Roselló-Catafau
Joan
J
Peralta
Carmen
C
D000818:Animals; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D005234:Fatty Liver / Q000150:complications*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D018972:Insulin-Like Growth Factor Binding Protein 3; D047495:PPAR gamma; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D048051:p38 Mitogen-Activated Protein Kinases