Postexposure treatment with aminophylline protects against phosgene-induced acute lung injury

Pretreatment with aminophylline has been shown to protect against various types of acute lung injury. Mechanisms responsible for protection are multifactorial but are thought to involve upregulation of cAMP. While previous studies focused on pretreatment, the present investigation examined post-treatment in rabbits following exposure to a lethal dose of the oxidant gas phosgene. Rabbits, 2-3 kg, were exposed to a cumulative dose of phosgene to attain a c x t exposure effect of 1500 ppm.min. Lungs were isolated in situ and perfused for 90-100 min after exposure with Krebs-Henseleit buffer at 40 mL/min. Pulmonary artery pressure (Ppa), tracheal pressure (Pt), and lung weight gain (lwg) were measured continuously. Leukotrienes 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 reduced GSH, GSSG, cAMP, and lipid peroxidation (TBARS). Post-treatment with aminophylline 80-90 min after exposure significantly lowered Ppa, Pt, and lwg. Aminophylline significantly reduced TBARS and perfusate LTC4/D4/E4, and prevented phosgene-induced decreases in lung tissue cAMP. These data suggest that protective mechanisms observed with aminophylline involve decreased LTC4/D4/E4-mediated pulmonary capillary permeability and attenuated lipid peroxidation. Direct antipermeability effects of cAMP on cellular contraction may also be important in protection against phosgene-induced lung injury.