17-Beta-estradiol protects the liver against warm ischemia/reperfusion injury and is associated with increased serum nitric oxide and decreased tumor necrosis factor-alpha

Surgery. 2002 Aug;132(2):302-9. doi: 10.1067/msy.2002.125718.


Background: Ischemia/reperfusion injury (I/R injury) to the liver can occur in low-flow states associated with trauma and shock and surgical procedures such as liver transplantation. Recent studies have shown that the administration of the female sex hormone 17-beta-estradiol after trauma-hemorrhage in animals restores depressed cardiac, hepatocellular, and immune functions. In this study we evaluated the effects of 17-beta-estradiol on I/R injury to the liver.

Methods: The medial lobe of the liver in normal male C57BL/6 mice was clamped at its base for 90 minutes. 17-Beta-estradiol was given 1 hour before I/R injury at 40 and 4000 microg/kg intraperitoneally. Biochemical analysis was performed, and liver biopsy specimens were obtained at 24 hours.

Results: A dose-dependent reduction in aspartate aminotransferase level was observed in animals (n = 8) given estradiol (243 +/- 23 IU/L) compared with saline-treated animals (902 +/- 42 IU/L, P <.001). The majority (90%) of the cytoprotective effect of estradiol was reverted by ICI 182,780 (a potent estrogen receptor antagonist). A significant increase in serum nitric oxide (NO) level was observed in animals given estradiol compared with controls; the effect was reversed by ICI 182,780 and N-nitro-L-arginine-methyl ester (an inhibitor of NO synthesis). A reduction in serum tumor necrosis factor-alpha was observed after injury in animals given estradiol compared with controls (30.2 +/- 11.1 vs 75.8 +/- 17.2 pg/mL, P <.001). Estradiol treatment significantly reduced liver necrosis, disintegration of hepatic cords, and neutrophil infiltration in an estrogen receptor-dependent manner.

Conclusions: Estradiol administration significantly reduced injury after I/R to the liver, an effect that is mainly receptor-mediated and is associated with increased serum NO, decreased TNF-alpha, and decreased number of neutrophils in liver biopsy specimens. Estrogen therapy may be important in clinical conditions associated with I/R injury to the liver.

MeSH terms

  • Animals
  • Cell Adhesion / drug effects
  • Cytoprotection
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / cytology
  • Estradiol / pharmacology*
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / cytology
  • Nitric Oxide / blood*
  • Reperfusion Injury / blood
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / pathology
  • Temperature
  • Tumor Necrosis Factor-alpha / metabolism*


  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Estradiol