EFFECT OF INDOMETHACIN ON INCREASES IN LEUKOTRIENE B-4 AND PULMONARY-EDEMA IN RESPONSE TO PHORBOL ESTER ADMINISTRATION IN DOGS

The administration of leukotrienes (LTs) into the pulmonary circulatio n results in edema formation and increased vascular permeability. We r eported previously that the administration of phorbol myristate acetat e (PMA, 20 mu g/kg) to intact anesthetized dogs results in a reduction in circulating white blood cells as well as the development of pulmon ary edema concomitant with the appearance of LTs in the lungs. In cont rast, when a smaller dose of PMA (10 mu g/kg) was administered, neithe r extravascular lung water nor LTs increased, although there was a sim ilar reduction in circulating white blood cells. In the present study, we used a property of indomethacin, namely, its capacity to augment t he formation of LTs, to examine further the relationship between LT ge neration and pulmonary edema formation in response to PMA administrati on. In intact pentobarbital-anesthetized dogs pretreated with saline ( N = 9), the administration of PMA at a dose of 10 mu g/kg, i.v., did n ot result in any change in extravascular lung water or in LTB(4) prese nt in bronchoalveolar lavage fluid (BALF). In contrast, in six animals pretreated with indomethacin (5 mg/kg), the administration of this do se of PMA resulted in increases in both extravascular lung water (P < 0.05) and LTB(4) (P < 0.05) in BALF. These results provide support for the hypothesis that leukotrienes are requisite for PMA induced increa ses in extravascular lung water.