Extension of Oxygen Tolerance by Treatment with Endotoxin: Means to Improve Its Potential Therapeutic Safety in Man

Treatment of adult rats with low doses of bacterial lipopolysaccharide (endotoxin) consistently results in a marked protective effect against O2-induced lung damage and lethality. We report here two means to improve the therapeutic ratio of endotoxin (ratio of dose producing desired beneficial effect/dose producing undesired toxic effects), which could make it a more acceptable pharmacologic agent for possible use in patients who require prolonged hyperoxic therapy. (a) Rats made "tolerant" to the lethal/toxic effects of high doses of endotoxin (25 mg/kg) by pretreatment with very low doses of endotoxin (10 ng----10 micrograms/kg) were found to still respond to a standard protective dose of endotoxin (500 micrograms/kg) with marked resistance to O2 toxicity. (Survival in greater than 95% O2 X 72 h = 19/20 (95%), vs. 4/17 (24%) for controls.) (b) Two chemically modified native endotoxin preparations ("endotoxoids"), with approximately 100 X decreased toxic potential, were found to have retained their ability to protect adult rats from prolonged hyperoxic exposure (90%-100% survival rates). These two experimental manipulations (use of the "endotoxin tolerance" phenomenon and treatment with partially detoxified "endotoxoids") were associated with increased lung antioxidant enzyme activities during O2 exposure in the treated animals. Continued research may eventuate in the possible clinical application of a safe form of endotoxin treatment for the prevention of O2 toxicity in humans.