Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion.
Glutathione is a tripeptide important in a number of diverse cellular functions including enzymatic reactions involved in prostaglandin endoperoxide metabolism. We have previously reported that cyclophosphamide administration to rats results in acute lung injury manifested by increased bronchoalveolar lavage albumin concentrations. In the current study we examine whether cyclophosphamide treatment affects pulmonary glutathione stores or bronchoalveolar endoperoxide metabolic product levels and whether these effects may be related to acute lung injury caused by the drug. We show that cyclophosphamide treatment causes a dose-dependent reduction in pulmonary glutathione stores 4 h after drug administration. In addition, acute lung injury as the result of cyclophosphamide can be abrogated by coadministration of oxothiazolidine carboxylate, an intracellular cysteine delivery system that also reverses pulmonary glutathione depletion induced by cyclophosphamide in our study. Finally, cyclophosphamide treatment reduces prostaglandin E2 concentrations in bronchoalveolar lavage and alveolar macrophage culture supernatant in a dose-dependent fashion and increases bronchoalveolar thromboxane concentrations in low dose-treated animals. These effects are reversed to a variable degree by coadministration of oxothiazolidine carboxylate. Our study suggests in vivo pulmonary arachidonic acid metabolism and cyclophosphamide-induced acute lung injury are modulated by cellular glutathione stores. These findings may have important implications for the treatment of acute lung injury.
Cooper
J A
JA
Pulmonary Section, Veterans Administration Medical Center, Birmingham 35233.
Merrill
W W
WW
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000032:analysis / Q000166:cytology; D003520:Cyclophosphamide / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D011449:Prostaglandin Endoperoxides / Q000032:analysis / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D011916:Rats, Inbred F344; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D011449:Prostaglandin Endoperoxides; D013844:Thiazoles; D053778:Thiazolidines; D003520:Cyclophosphamide; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid