title: Intratracheal administration of DBcAMP attenuates edema formation in phosgene-induced acute lung injury.
abstract: Phosgene, a toxic gas widely used as an industrial chemical intermediate, is known to cause life-threatening latent noncardiogenic pulmonary edema. Mechanisms related to its toxicity appear to involve lipoxygenase mediators of arachidonic acid (AA) and can be inhibited by pretreatment with drugs that increase adenosine 3',5'-cyclic monophosphate (cAMP). In the present study, we used the isolated buffer-perfused rabbit lung model to investigate the mechanisms by which cAMP protects against phosgene-induced lung injury. Posttreatment with dibutyryl cAMP (DBcAMP) was given 60-85 min after exposure by an intravascular or intratracheal route. Lung weight gain (LWG) was measured continuously. AA metabolites leukotriene (LT) C4, LTD4, and LTE4 and 6-ketoprostaglandin F1 alpha were measured in the perfusate at 70, 90, 110, 130, and 150 min after exposure. Tissue malondialdehyde and reduced and oxidized glutathione were analyzed 150 min postexposure. Compared with measurements in the lungs of rabbits exposed to phosgene alone, posttreatment with DBcAMP significantly reduced LWG, pulmonary arterial pressure, and inhibited the release of LTC4, LTD4, and LTE4. Intratracheal administration of DBcAMP was more effective than intravascular administration in reducing LWG. Posttreatment also decreased MDA and protected against glutathione oxidation observed with phosgene exposure. We conclude that phosgene causes marked glutathione oxidation, lipid peroxidation, release of AA mediators, and increases LWG. Posttreatment with 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.
authors.affiliation: Physiology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Sciuto
authors.forename: P T
authors.initials: PT
authors.lastname: Strickland
authors.forename: T P
authors.initials: TP
authors.lastname: Kennedy
authors.forename: Y L
authors.initials: YL
authors.lastname: Guo
authors.forename: G H
authors.initials: GH
authors.lastname: Gurtner
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D003994:Bucladesine / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007442:Intubation, Intratracheal; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D010705:Phosgene; D011506:Proteins / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011817:Rabbits
chemical_list: D001095:Arachidonic Acids; D015289:Leukotrienes; D011506:Proteins; D010705:Phosgene; D008315:Malondialdehyde; D015121:6-Ketoprostaglandin F1 alpha; D003994:Bucladesine; D005978:Glutathione