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 i.v.+i.t.); and phosgene-exposed isoproterenol-treated intratracheally (ISO i.t.). Treatment with ISO was administered as either a continuous intravascular infusion (24 microg min(-1)) from the beginning to end of perfusion (i.v.) and a 24-microg intratracheal bolus (i.t.) or just an i.t. 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 x 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 i.v.+i.t. or i.t. routes 50+ min after phosgene exposure significantly lowered Ppa, Pt and lwg. Phosgene-exposed rabbits post-treated with ISO i.t. 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 (i.v.+i.t.) 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 i.t. and ISO i.v.+i.t. 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.
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Pharmacology Division, Neurotoxicology Branch, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Strickland
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Gurtner
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D000818:Animals; D000242:Cyclic AMP / Q000032:analysis; D005978:Glutathione / Q000032:analysis; D007545:Isoproterenol / Q000008:administration & dosage / Q000627:therapeutic use*; D017997:Leukotriene C4 / Q000032:analysis; D017998:Leukotriene D4 / Q000032:analysis; D017999:Leukotriene E4 / Q000032:analysis; D008168:Lung / Q000378:metabolism; D008297:Male; D010705:Phosgene / Q000506:poisoning*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors
D010705:Phosgene; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; D000242:Cyclic AMP; D005978:Glutathione; D007545:Isoproterenol