Endotoxin tolerance protects against local hepatic ischemia/reperfusion injury in the rat.
Liver surgery and liver transplantation as well as circulatory shock are often associated with hepatic ischemia/reperfusion (I/R) injury. Recent evidence suggests that TNF-alpha plays a central role in I/R injury and, therefore, down-regulation of TNF-alpha seems to be a promising way to protect against the deleterious consequences of I/R. Endotoxin tolerance represents a state of unresponsiveness to endotoxin and is associated with diminished TNF-alpha production. Thus, the effect of endotoxin tolerance on hepatic I/R injury of the liver was investigated in a rat model. I/R injury was induced by temporary ischemia of the left lateral liver lobe for 90 min followed by a 3 h observation period of reperfusion. I/R injury resulted in functional hepatic disorder characterized by a decrease both in bile flow and bile acid concentration and 50% mortality. This was prevented by induction of endotoxin tolerance. Hepatic TNF-alpha mRNA expression after I/R of the liver was determined by RT-PCR. In untreated rats, TNF-alpha mRNA was induced in the liver 60 min after reperfusion and further increased until 3 h after reperfusion. In contrast, in endotoxin-tolerant rats, no increases in TNF-alpha mRNA expression were detected. This suggests that induction of endotoxin tolerance protects against hepatic I/R injury possibly via down-regulation of intra-organ TNF-alpha expression.
Fernández
E D
ED
Department of General Surgery, Mannheim Medical School, University of Heidelberg, Mannheim, Germany. emilio.dominguez@chir.ma.uni-heidelberg.de
Flohé
S
S
Siemers
F
F
Nau
M
M
Ackermann
M
M
Ruwe
M
M
Schade
F U
FU
D000818:Animals; D001483:Base Sequence; D001646:Bile / Q000502:physiology; D001647:Bile Acids and Salts / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D004731:Endotoxins / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D001647:Bile Acids and Salts; D017931:DNA Primers; D004731:Endotoxins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha