Endotoxin tolerance protects against local hepatic ischemia/reperfusion injury in the rat

Liver surgery and liver transplantation as well as circulatory shuck are of ten associated with hepatic ischemia/reperfusion (I/R) injury. Recent evide nce suggests that TNF-alpha plays a central role in I/R injury and, therefo re, down-regulation of TNF-alpha seems to be a promising way to protect aga inst the deleterious consequences of I/R. Endotoxin tolerance represents a state of unresponsiveness to endotoxin and is associated with diminished TN F-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 b y a 3 h observation period of reperfusion. I/R injury resulted in functiona l hepatic disorder characterized by a decrease both in bile flow and bile a cid concentration and 50% mortality. This was prevented by induction of end otoxin 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 re pel fusion. In contrast, in endotoxin-tolerant rats, no increases: in TNF-a lpha mRNA expression were detected. This suggests that induction of endotox in tolerance protects against hepatic I/R injury possibly via down-regulati on of intra-organ TNF-alpha expression.