Amelioration of tumor necrosis factor release by cyclosporine in warm ischemia/reperfusion injury of the rat liver: with special reference to hepatic ultrastructure.
Mechanisms by which an immunosuppressant (cyclosporine, CsA) ameliorates warm ischemic injury of the liver were studied. Female Sprague-Dawley rats were subjected to 60-min normothermic liver ischemia. Animals were assigned to one of two groups: group I, controls with vehicle treatment; group II, treatment with CsA (10 mg/kg). CsA was given orally for 4 consecutive days prior to the induction of hepatic ischemia. In addition to a survival study, plasma levels of endotoxin, serum activity of tumor necrosis factor-alpha (TNF), and serum levels of aminotransferases were measured in blood samples collected from the suprahepatic vena cava, and hepatic ultrastructural alterations were examined under an electron microscope. The 7-day survival rate was significantly higher in the CsA-treated animals. In the control group, serum TNF levels were elevated following reperfusion and peaked at 3 h. When the values at 3 h post reflow were compared, the animals given CsA had significantly lower levels of TNF (170.0 +/- 30.5 pg/ml for group I, 67.6 +/- 13.7 for group II, mean +/- SEM; P < 0.05). The sinusoidal lining cells and hepatocytes were drastically destroyed at 6 h post reflow in the control group, although the degree of injury at 1-3 h was less severe. On the other hand, the endothelium and parenchymal liver cells in the CsA-treated group were well preserved at 6 h in comparison with those in the control group. Our data suggest that modulation of TNF production is one of the mechanisms through which CsA prevents the exacerbation of ischemia/reperfusion injury of the liver.
Ishii
T
T
First Department of Surgery, Oita Medical University, Hasama-machi, Oita 879-5593, Japan.
Kim
Y I
YI
Kawano
K
K
Tatsuma
T
T
Shimada
T
T
Kitano
S
S
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply* / Q000648:ultrastructure*; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D000637:Transaminases / Q000032:analysis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000378:metabolism
D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D000637:Transaminases