THE PROPHYLACTIC EFFECTS OF U75412E PRETREATMENT IN A SMOKE-INDUCED LUNG INJURY RABBIT MODEL

The effects of the lazaroid analogue U75412E 21-[4-(3-ethylamino-2-pyr idinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9]-(11)-triene-3,20-d ione) were examined in an acute lung injury rabbit model. Standard dos es of 0, 8 and 16 mM U75412E were aerosolized and ventilated into the lungs for 3 min. via an endotracheal tube. A 60 tidal volume dose of d iesel fuel-polycarbonate plastic smoke was then instilled, followed by mechanical ventilation for one hour. Pretreatment with 16 mM U75412E significantly increased blood PaO2 and pH values, and decreased blood PaCO2 as compared to smoke only exposures. It also significantly decre ased the total cell counts and granulocytes in bronchoalveolar lavage fluid, and the ability of pulmonary alveolar macrophages to produce tu mour necrosis factor-alpha ill vitro after cell isolation and culture. Histopathology indicated that 16 mM U75412E pretreatment attenuated i ncreases in wet lung/body weight ratios, inflammatory focus, and inter stitial oedema associated with smoke insult. In summary, U75412E pretr eatment may possess the potential to improve acute smoke-induced lung injury, in part, through modulation of tumour necrosis factor-alpha pr oduction from pulmonary alveolar macrophages.