We examined the effect of tumor necrosis factor a ITNF,) on the increase in pulmonary microvascular endothelial monolayer permeability induced by activated neutrophils (PMN). Layering of PMN onto endothelial monolayers followed by activation of PMN with phorbol 12-myristate 13-acetate (PMA) increased ""I-albumin clearance rate across the monolayers. Pretreatment of endothelial monolayers for 6 hr with TNF, (200 U/ml) potentiated the PMN-dependent increase in endothelial permeability, whereas 1 hr or 6 hr pretreatment of endothelial monolayers with 200 U/ml and 100 U/ml, respectively, TNF, did not enhance the reponse. Adherence of PMN to the endothelial cells was increased at 1 and 6 hr after TNF, (200 U/ml) treatment, but the adherence reponse was markedly greater following 6 hr of TNF, . The TNF, treatment of endothelial cells did not enhance neutrophil activation responses to PMA. Pretreatment of PMN with IB4, a MAb to the CD18 integrin, the common P subunit of the adhesion proteins LFA-1, Mac-1, and p150,95 of PMN, reduced the increases in PMN adherence and the endothelial monolayer permeability induced by the 6 hr TNF, treatment. In contrast, pretreatment of PMN with OKM-1, a MAb to the CD11 b epitope (a-subunit), had no effect on the adherence and the potentiation of the increase in permeability. The potentiation of the PMN-dependent permeability increase and enhanced endothelial adhesivity at 6 hr after TNF, priming of endothelial cells was dependent on protein synthesis. The results indicate that protein synthesis-dependent expression of an endothelial ligand for CD18 and resultant endothelial hyperadhesiveness potentiates the PMN-mediated increase in endothelial permeability after TNF,, activation of endothelial cells. The priming of endothelial cells by TNF, may be a critical step in the mediation of endothelial injury.