Endotoxin tolerance in rats:: influence on LPS-induced changes in excretory liver function

Objective and design: We investigated in a rat model of endotoxic shock whether endotoxin tolerance (ETT) prevents lipopolysaccharide (LPS) associated lethality and studied the initial function of liver response to LPS. Animals: Male Sprague-Dawley rats. Treatment: ETT was induced by i.p. injection of LPS (Salmonella friedenau) intraperitoneally over 5 days. Rats (n = 6 each group) received 1 mg LPS/kg b. w. intravenously (Salmonella friedenau). The common bile duct was then canalized and bile was collected every 60 min for 6 h. 1 h after LPS-application liver biopsies were taken for determination of TNF-alpha by RT-PCR. Sham operated animals (n = 6 each group) were treated identically but without application of LPS. Results: All ETT animals survived the duration of the experiment whereas non-tolerant animals (NETT) died before the end of the experiment (5/6). NETT animals showed a continuous decrease in bile flow after 240 min. The amount of bile acids was significantly lower (ANOVA) in NETT animals than in sham operated controls or ETT-animals. Analysis of TNF-alpha mRNA expression in the liver revealed an upregulation 1 h after LPS application, which was significantly lower in LPS-tolerant animals. Conclusions: Our results show that excretory liver failure and death subsequent to intravenous LPS application can be successfully counteracted by induction of ETT.