Inhaled bacterial lipopolysaccharide (LPS - endotoxin) elicits a number of inflammatory events in the lung, perhaps the most dangerous being an increase in pulmonary vascular permeability. In order to determine the primary inflammatory mediators involved in the pulmonary response to LPS, permeability measurements were made in hamsters exposed to aerosols of Enterobacter agglomerans LPS. Aerosolized LPS resulted in a significant increase in pulmonary capillary permeability as detected by leakage of I-BSA from the pulmonary vasculature of hamsters. This change could be a serious prelude to further injury. By using the selective pharmacological inhibitors indomethacin, FPL-55712 (a leukotriene receptor inhibitor), naloxone, and cobra venom factor (a complement inhibitor) together with aerosol challenges, identification of the major mediators was achieved. The loss in permeability was highly dependent on complement and Prostaglandins and somewhat dependent on leukotrienes. These results identify possible mechanisms by which pulmonary capillary endothelial cells may be altered to lead to permeability increases in the lung.