Background: Prior administration of endotoxin has conferred resistance to tissue damage in a number of models of organ injury. The mechanisms by which this resistance is conferred are enigmatic. Recognizing that enhanced tissue oxidative stress may be a feature of endotoxin-associated injury and is present in many models of tissue injury, we questioned whether the beneficial effect conferred by endotoxin is dependent on the up-regulation of antioxidant defenses.
Experimental design: We employed the glycerol model of acute renal failure (Gly-ARF), a model in which oxidant damage occurs in the kidney and other organs as a result of rhabdomyolysis and hemolysis. Rats were pretreated with endotoxin 24 hours before, or at the time of, induction of Gly-ARF. Renal functional studies and assessment of renal antioxidant status were performed. The effect of prior treatment with endotoxin was also examined in models of methemoglobin-induced and ischemic ARF.
Results: Renal function was improved in rats pretreated with endotoxin but worsened in rats subjected to Gly-ARF and endotoxin simultaneously. Endotoxin induced heme oxygenase activity and ferritin content in the kidney but did not induce other antioxidant systems such as catalase and glutathione peroxidase. Treatment with a competitive inhibitor of heme oxygenase blocked endotoxin-induced protection on days 2 and 3, while markedly attenuating the protective effect on day 1. Pretreatment with endotoxin reduced renal injury induced by methemoglobin, but not ischemia.
Conclusions: The resistance to injury conferred by endotoxin in Gly-ARF involves induction of an antioxidant response, consisting of increased heme oxygenase and ferritin synthesis. This coupled response allows degradation of heme as well as chelation of iron, thus decreasing oxidant-mediated tissue injury. This novel mechanism of endotoxin-induced resistance may be applicable not only to Gly-ARF but also to other models of tissue injury in which enhanced oxidative stress is implicated.