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.
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.
Eckhoff
Devin E
DE
Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, 35294, USA.
Bilbao
Guadalupe
G
Frenette
Luc
L
Thompson
J Anthony
JA
Contreras
Juan L
JL
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D004958:Estradiol / Q000494:pharmacology*; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology; D009569:Nitric Oxide / Q000097:blood*; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013696:Temperature; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004958:Estradiol