POSTEXPOSURE TREATMENT WITH ISOPROTERENOL ATTENUATES PULMONARY-EDEMA IN PHOSGENE-EXPOSED RABBITS

This study investigated the post-treatment effect of isoproterenol (IS O) on pulmonary parameters in rabbits whole-body-exposed to a lethal d ose of the toxic gas phosgene, Phosgene is widely used in industry as a chemical intermediate for the production of plastics, drugs and poly urethane products. The results of this study are from five study group s: Id-min perfused baseline; uninjured controls exposed to air; phosge ne-exposed; phosgene-exposed isoproterenol-treated intravascularly and intratracheally (ISO IV+IT); and phosgene-exposed isoproterenol-treat ed intratracheally (ISO IT). Treatment with ISO was administered as ei ther a continuous intravascular infusion (24 mu g min(-1)) from the be ginning to end of perfusion (IV) and a 24-mu g intratracheal bolus (IT ) or just an IT bolus immediately prior to the start of perfusion. Rab bits of 2.5-3 kg were exposed to a cumulative dose of phosgene to atta in a concentration X time exposure-effect of 1500 ppm.min. Lungs were isolated in situ and perfused 50-60 min after the start of exposure wi th Krebs-Henseleit buffer at 40 ml.min(-1). Pulmonary artery pressure (Ppa), tracheal pressure (Pt) and lung weight gain (lwg) were continuo usly measured. Leukotrienes (LT) C-4/D-4/E-4 were measured in the perf usate every 20 min during perfusion. At the immediate conclusion of th e experiment, lung tissue was frozen in liquid N-2 and analyzed for gl utathione (GSH) and cyclic 3',5'-adenosine monophosphate (cAMP), Post- treatment with ISO by either IV+IT or IT routes 50+ min after phosgene exposure significantly lowered Ppa, Pt and lwg, Phosgene-exposed rabb its post-treated with ISO IT had significantly higher levels of reduce d GSH (3 +/- 0.4 nmol mg(-1) protein), GSR/GSSG ratios (3.3 +/- 0.6 nm ol mg(-1) protein) and percentage of total as reduced GSH (75 +/- 2.5% ) compared with phosgene-exposed rabbits: 1.9 +/- 0.3, 2 +/- 0.3 and 5 8 +/- 6.3%, respectively. The ISO (IV+IT) post-treatment route signifi cantly increased reduced GSH (6.2 +/- 1.7 nmol mg(-1) protein), GSH/GS SG ratio (5.9 +/- 0.8 nmol mg(-1) protein) and percentage of total as reduced GSH (85 +/- 1.7%) when compared to the phosgene-only group. Th e ISO IT and ISO IV+IT treatments significantly reduced perfusate LTC4 /D-4/E-4 150 min after the start of exposure by 90% and 48%, respectiv ely. These data suggest that protective mechanisms for ISO involve red uced vascular pressure, decreased LTC4/D-4/E-4-mediated pulmonary capi llary permeability and a favorable lung tissue redox state compared wi th untreated phosgene-exposed rabbits. (C) 1998 John Wiley & Sons, Ltd .