Warm ischemia-reperfusion injury is decreased by tacrolimus in steatotic rat liver.
Ischemia-reperfusion (I-R) injury is poorly tolerated by fatty livers, most probably secondary to reduced cellular adenosine triphosphate (ATP) levels. We investigated the effectiveness of tacrolimus pretreatment on fatty liver I-R injury in obese Zucker rats. Tacrolimus (0.3 mg/kg, intravenously) was injected 24 hours before a 75-minute ischemic period and rats were sacrificed 6 hours later. Tacrolimus modified the response to I-R observed in obese Zucker rats, when compared to nontreated obese rats: a significant reduction in hepatocyte necrosis was associated with a significant increase in hepatocyte apoptosis. In addition, cell necrosis and apoptosis were significantly and inversely correlated in lean nontreated and treated obese Zucker rats following I-R. Tacrolimus also significantly increased the hepatic ATP levels, reduced in nontreated obese rats, toward values found in lean Zucker rat livers. This protective effect of tacrolimus was further confirmed in vivo by a significantly improved survival following pretreatment with tacrolimus, 24 hours prior to ischemia. In conclusion, in obese Zucker rat livers, tacrolimus pretreatment reversed the I-R injury toward the one found in lean Zucker rats. The correlations between ATP levels and the opposite changes in necrosis and apoptotic pathways strongly suggest a cause-effect relationship between tacrolimus and changes in ATP levels.
Laurens
Marina
M
Laboratoire de Recherches Chirurgicales, Université de Nice Sophia-Antipolis, Nice, France.
Scozzari
Gitana
G
Patrono
Damiano
D
St-Paul
Marie-Christine
MC
Gugenheim
Jean
J
Huet
Pierre-Michel
PM
Crenesse
Dominique
D
D000818:Animals; D001707:Biopsy, Needle; D001835:Body Weight; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D007150:Immunohistochemistry; D008102:Liver Circulation; D008111:Liver Function Tests; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D009336:Necrosis / Q000473:pathology / Q000517:prevention & control; D011336:Probability; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D018709:Statistics, Nonparametric; D015996:Survival Rate; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors
D016559:Tacrolimus