INTRATRACHEAL ADMINISTRATION OF DBCAMP ATTENUATES EDEMA FORMATION IN PHOSGENE-INDUCED ACUTE LUNG INJURY

Phosgene, a toxic gas widely used as an industrial chemical intermedia te, is known to cause life-threatening latent noncardiogenic pulmonary edema. Mechanisms related to its toxicity appear to involve lipoxygen ase mediators of arachidonic acid (AA) and can be inhibited by pretrea tment with drugs that increase adenosine 3',5'-cyclic monophosphate (c AMP). In the present study, we used the isolated buffer-perfused rabbi t lung model to investigate the mechanisms by which cAMP protects agai nst phosgene-induced lung injury. Posttreatment with dibutyryl cAMP (D BcAMP) was given 60-85 min after exposure by an intravascular or intra tracheal route. Lung weight gain (LWG) was measured continuously. AA m etabolites leukotriene (LT) C-4, LTD(4), and LTE(4) and 6-ketoprostagl andin F-1 alpha were measured in the perfusate at 70, 90, 110, 130, an d 150 min after exposure. Tissue malondialdehyde and reduced and oxidi zed glutathione were analyzed 150 min postexposure. Compared with meas urements in the lungs of rabbits exposed to phosgene alone, posttreatm ent with DBcAMP significantly reduced LWG, pulmonary arterial pressure , and inhibited the release of LTC(4), LTD(4), and LTE(4). Intratrache al administration of DBcAMP was more effective than intravascular admi nistration in reducing LWG. Posttreatment also decreased MDA and prote cted against glutathione oxidation observed with phosgene exposure. We conclude that phosgene causes marked glutathione oxidation, lipid per oxidation, release of AA mediators, and increases LWG. Posttreatment w ith DBcAMP attenuates these effects, not only by previously described inhibition of pulmonary endothelial or epithelial cell contraction but also by inhibition of AA-mediator production and a novel antioxidant effect.