Blockade of the Fas/Fas ligand interaction suppresses hepatocyte apoptosis in ischemia-reperfusion rat liver

Apoptosis. 2008 Aug;13(8):1013-21. doi: 10.1007/s10495-008-0234-5.

Abstract

Hepatic ischemia-reperfusion injury remains a significant problem for liver surgery, including transplantation, and apoptosis has been implicated in this type of hepatic injury. Here we found that through the Fas/Fas ligand interaction apoptosis is involved in the late phase of hepatic ischemia-reperfusion injury. The appearance of apoptotic hepatocytes increases significantly after reperfusion, reaching a maximum 12 h after reperfusion. The transcription levels of Fas and Fas ligand are increased after reperfusion. Fas is expressed on hepatocytes, while Fas ligand is expressed on infiltrating immune cells. A close spatial and temporal association of Fas expression and apoptotic cells is demonstrated in the histological observation. These results suggest that infiltrating cells induce apoptosis of hepatocytes through the Fas/Fas ligand interaction, leading to hepatocyte injury. Furthermore, an injection of anti-Fas antibody or neutralizing anti-Fas ligand antibody results in a dramatic decrease in the occurrence of hepatocyte apoptosis and hepatic infiltration of macrophages and natural killer cells as well as liver injury. Our results suggest that blockage of the Fas/Fas ligand interaction is a promising strategy for suppression of hepatic ischemia-reperfusion injury.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / physiology
  • Fas Ligand Protein / antagonists & inhibitors
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism*
  • Hepatocytes / metabolism*
  • Liver / blood supply
  • Liver / metabolism*
  • Liver / surgery
  • Liver Failure / metabolism
  • Liver Failure / physiopathology
  • Liver Failure / prevention & control
  • Macrophages / drug effects
  • Macrophages / physiology
  • Male
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Time Factors
  • fas Receptor / antagonists & inhibitors
  • fas Receptor / genetics
  • fas Receptor / metabolism*

Substances

  • Antibodies
  • Fas Ligand Protein
  • RNA, Messenger
  • fas Receptor