Blockade of the Fas/Fas ligand interaction suppresses hepatocyte apoptosis in ischemia-reperfusion rat liver.
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.
Department of Endocrine, Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Hiroo
H
Nakajima
Naruhiko
N
Mizuta
Ikuya
I
Fujiwara
Koichi
K
Sakaguchi
Hiromitsu
H
Ogata
Junji
J
Magae
Hideo
H
Yagita
Takehiko
T
Koji
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000601:surgery; D017093:Liver Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D019014:fas Receptor