Post-exposure treatment with isoproterenol attenuates pulmonary edema in phosgene-exposed rabbits

This study investigated the post-treatment effect of isoproterenol (ISO) on pulmonary parameters in rabbits whole-body-exposed to a lethal dose of the toxic gas phosgene. Phosgene is widely used in industry as a chemical intermediate for the production of plastics, drugs and polyurethane products. The results of this study are from five study groups: 10-min perfused baseline; uninjured controls exposed to air; phosgene-exposed; phosgene-exposed isoproterenol-treated intravascularly and intratracheally (ISO IV+IT); and phosgene-exposed isoproterenol-treated intratracheally (ISO IT). Treatment with ISO was administered as either a continuous intravascular infusion (24 μgmin^-1) from the beginning to end of perfusion (IV) and a 24-μg intratracheal bolus (IT) or just an IT bolus immediately prior to the start of perfusion. Rabbits of 2.5-3 kg were exposed to a cumulative dose of phosgene to attain 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 with Krebs-Henseleit buffer at 40 ml min^-1. Pulmonary artery pressure (Ppa), tracheal pressure (Pt) and lung weight gain (lwg) were continuously measured. Leukotrienes (LT) C₄/D₄/E₄, were measured in the perfusate every 20 min during perfusion. At the immediate conclusion of the experiment, lung tissue was frozen in liquid N₂ and analyzed for glutathione (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 rabbits post-treated with ISO IT had significantly higher levels of reduced GSH (3 ± 0.4 nmol mg^-1 protein), GSH/GSSG ratios (3.3 ± 0.6 nmol 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 58 ± 6.3%, respectively. The ISO (IV+IT) post-treatment route significantly increased reduced GSH (6.2 ± 1.7 nmol mg^-1 protein), GSH/GSSG 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. The ISO IT and ISO IV+IT treatments significantly reduced perfusate LTC₄/D₄/E₄ 150 min after the start of exposure by 90% and 48%, respectively. These data suggest that protective mechanisms for ISO involve reduced vascular pressure, decreased LTC₄/D₄/E₄-mediated pulmonary capillary permeability and a favorable lung tissue redox state compared with untreated phosgene-exposed rabbits.