ACTIVATED PROTEIN-C PREVENTS LPS-INDUCED PULMONARY VASCULAR INJURY BYINHIBITING CYTOKINE PRODUCTION

We investigated the effect of activated protein C (APC) on pulmonary v ascular injury and the increase in tumor necrosis factor (TNF) levels in lipopoly- saccharide (LPS)-treated rats to determine whether APC re duces LPS-induced endothelial damage by inhibiting cytokine production . Intravenously administered LPS (5 mg/kg) induced pulmonary vascular injury, as indicated by an increase in the lung wet-to-dry weight rati o. LPS-induced pulmonary vascular injury was prevented by APC but not by active site-blocked factor Xa [dansyl glutamyl-glycyl-arginyl chlor omethyl detone-treated activated factor X (DEGR-Xa)], a selective inhi bitor of thrombin generation, or inactivated APC [diisopropyl fluoroph osphate-treated APC (DIP-APC)]. APC, but not DEGR-Xa or DIP-APC, signi ficantly inhibited the LPS-induced increase in the plasma level of TNF . APC significantly inhibited the production of TNF by LPS-stimulated monocytes in a dose-dependent fashion in vitro, but DIP-APC did not. A PC did not inhibit the functions of activated neutrophils in vitro. Th ese findings suggest that APC prevented LPS-induced pulmonary vascular injury by inhibiting TNF production by monocytes and not via its anti coagulant activity. The serine protease activity of APC appears to be essential for inhibition of TNF production.