Pulmonary oxygen toxicity in rats: prevention by pyrogenic diphosphoryl lipid A and potentiation by nontoxic monophosphoryl lipid A and lipid X.
Pretreatment with gram-negative bacterial endotoxin protects rats from the lethal intrathoracic edema produced by continuous exposure to greater than 95% O2 for 3 days. To help elucidate structure-activity relationships of endotoxin, we administered lipid part-structures of endotoxin intraperitoneally (at dosages up to 5.0 mg/kg) to male Sprague-Dawley rats prior to exposure to greater than 99% O2 (at 760 mm Hg) for 72 hr. We found that Salmonella minnesota mutant Re595 diphosphoryl lipid A protected rats from O2 toxicity as effectively as the parent S. minnesota endotoxin molecule at equimolar concentration. Diphosphoryl lipid A exhibited less acute toxicity (2 hr post-treatment hypothermia) than did endotoxin, although both produced prolonged fevers (greater than 24 hr) and similar patterns of protection in O2. In contrast, nontoxic lipid X (2,3-diacylglucosamine 1-phosphate) and monophosphoryl (1-dephospho) lipid A potentiated pulmonary O2 toxicity. We conclude that within the range of dosages investigated, diphosphoryl lipid A is the minimal essential structure responsible for the protection of rats from O2 toxicity by endotoxin.
Smith
R M
RM
Department of Physiology, John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu 96822.
D000818:Animals; D004357:Drug Synergism; D004731:Endotoxins / Q000494:pharmacology; D004926:Escherichia coli; D006017:Glycolipids / Q000494:pharmacology* / Q000633:toxicity; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D010100:Oxygen / Q000633:toxicity*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D004731:Endotoxins; D006017:Glycolipids; D008050:Lipid A; C049596:diphosphoryl lipid A; C044283:lipid X; C048436:monophosphoryl lipid A; D010100:Oxygen