Amelioration of tumor necrosis factor release by cyclosporine in warm ischemia/reperfusion injury of the rat liver: with special reference to hepatic ultrastructure

J Hepatobiliary Pancreat Surg. 1999;6(3):267-74. doi: 10.1007/s005340050117.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cyclosporine / pharmacology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Immunosuppressive Agents / pharmacology*
  • Liver / blood supply*
  • Liver / ultrastructure*
  • Microscopy, Electron
  • Rats
  • Rats, Sprague-Dawley
  • Reference Values
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / mortality
  • Reperfusion Injury / pathology
  • Survival Rate
  • Transaminases / analysis
  • Transaminases / metabolism
  • Tumor Necrosis Factor-alpha / analysis*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Immunosuppressive Agents
  • Tumor Necrosis Factor-alpha
  • Cyclosporine
  • Transaminases