A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis.
Apoptosisis activated during the early phase of reperfusion after liver ischemia and after liver transplantation in animals. However, the molecular basis of ischemia-induced cell death remains poorly understood. In this study we show that hepatocytes from ischemic liver lobes undergo apoptosis after reperfusion. In vivo pretreatment of rats with a specific inhibitor of caspases abrogates the apoptotic response in ischemic liver lobes. Inhibition of apoptosis can be accounted for by total inhibition of caspase activation as assessed in an enzymatic assay and by specific affinity labeling. Treatment with a caspase inhibitor fully protects rats from death induced by ischemia/reperfusion. These findings indicate that liver injury after ischemia/reperfusion can be prevented by inhibition of caspases. Thus, caspase inhibitors may have important therapeutic implications in liver ischemic diseases and after liver transplantation.
Cursio
R
R
Laboratoire de Recherches Chirurgicales, Université de Nice-Sophia- Antipolis, Faculté de Médecine, Nice Cedex 2, France.
Gugenheim
J
J
Ricci
J E
JE
Crenesse
D
D
Rostagno
P
P
Maulon
L
L
Saint-Paul
M C
MC
Ferrua
B
B
Auberger
A P
AP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000098:blood supply* / Q000473:pathology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew