ROLE OF PLATELET-ACTIVATING-FACTOR IN MEDIATING TUMOR-NECROSIS-FACTOR ALPHA-INDUCED PULMONARY VASOCONSTRICTION AND PLASMA-LYMPH PROTEIN-TRANSPORT

We assessed the role of platelet-activating factor (PAF) in mediating the pulmonary hemodynamic and lymph flow responses to tumor necrosis factor-alpha (TNF-alpha). The effects of the PAF receptor antagonist WEB 2086 on TNF-alpha-induced pulmonary vasoconstriction and increased pulmonary transvascular plasma-lymph protein transport were examined. Control (n = 7) and WEB-2086-pretreated (n = 7) sheep prepared with chronic lung lymph fistulas were challenged with recombinant human TNF-alpha (12-mu-g/kg over 0.5 h). Ex vivo challenge of platelet-rich plasma (PRP) with 10(-8) M PAF resulted in aggregation of platelets from control TNF-challenged sheep, but not of platelets from WEB-treated sheep similarly challenged with TNF. The control TNF-alpha-challenged sheep developed hemoconcentration, leukopenia, and neutropenia. TNF-alpha resulted in increases in pulmonary arterial pressure (PpaBAR) and pulmonary vascular resistance (PVR) within 15 min, and the values were sustained for the 5-h experiment duration. Pulmonary lymph flow (Qlym) and pulmonary transvascular protein clearance rate (Qlym x lymph-to-plasma protein concentration) were increased within 30 min and remained elevated for 5 h. The WEB-2086-treated sheep developed similar leukopenia and neutropenia after TNF-alpha challenge, but the initial increases in PpaBAR and PVR were significantly reduced (p < 0.05). However, WEB 2086 did not prevent the threefold increases in Qlym and transvascular protein clearance induced with TNF-alpha. We conclude that PAF does not mediate the TNF-alpha-induced increase in pulmonary plasma-lymph protein transport (i.e., lung vascular permeability), but that PAF contributes to the initial pulmonary vasoconstriction after TNF-alpha challenge, and, thus, may increase the pulmonary capillary hydrostatic by this mechanism.