INHIBITION OF CYTOCHROME-P-450 ATTENUATES HYPOXEMIA OF ACUTE LUNG INJURY IN DOGS

The intravenous administration of ethchlorvynol (ECV), in dogs, result ed in an acute lung injury (ALI) characterized by a 200 +/- 80% increa se in venous admixture and a 142 +/- 30% increase in extravascular lun g water (EVLW). Pretreatment with the cytochrome P-450 inhibitor 8-met hoxypsoralen prevented the ECV-induced increase in venous admixture bu t not the increased EVLW. These findings parallel those reported for c yclooxygenase inhibition in ECV-induced ALI and suggest that an arachi donic acid (AA) metabolite of pulmonary cytochrome P-450 activity may mediate the increase in venous admixture of ALI. We demonstrate that c anine pulmonary microsomes metabolize [1-C-14]AA to a variety of produ cts, including the cytochrome P-450 metabolites 5,6-, 8,9-, 11,12-, an d 14,15-epoxyeicosatrienoic acid (EET). In prostaglandin F-2 alpha-con tracted, isolated pulmonary venous rings, 5,6-EET induced relaxation i n a concentration-dependent manner. This action of 5,6-EET was prevent ed by indomethacin (10(-5) M). These results suggest that 5,6-EET may serve as the cyclooxygenase-dependent endogenous pulmonary vasodilator responsible for the increase in venous admixture of ECV-induced ALI.