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 micrograms/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 (Ppa) 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 Ppa and PVR were significantly reduced (p less than 0.05). However, WEB 2086 did not prevent the threefold increases in Qlym and transvascular protein clearance induced with TNF alpha.(ABSTRACT TRUNCATED AT 250 WORDS)