ACTIVATED PROTEIN-C ATTENUATES ENDOTOXIN-INDUCED PULMONARY VASCULAR INJURY BY INHIBITING ACTIVATED LEUKOCYTES IN RATS

We investigated the effect of activated protein C (APC) on lipopolysac charide (LPS)-induced pulmonary vascular injury in rats to investigate the possible usefulness of APC as a treatment for adult respiratory d istress syndrome. Intravenously administered LPS (5 mg/kg) significant ly increased pulmonary vascular permeability. APC prevented the LPS-in duced increase in pulmonary vascular permeability observed at 6 hours. Heparin plus antithrombin III (ATIII) and active site-blocked factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, inhibited LPS-induced coagulopathy but did not prevent LPS-induced pulmonary vas cular injury. LPS-induced pulmonary vascular injury was significantly attenuated in rats with nitrogen mustard-induced leukocytopenia and in rats treated with ONO-5046, a potent granulocyte elastase inhibitor. Administration of LPS also increased pulmonary accumulation of leukocy tes, as evaluated by measurement of myeloperoxidase activity in the lu ngs. APC significantly reduced LPS-induced increases in pulmonary accu mulation of leukocytes at 1 hour. Neither ATIII plus heparin nor DEGR- Xa inhibited leukocyte accumulation. Active site-blocked APC (DIP-APC) prevented neither the LPS-induced pulmonary accumulation of leukocyte s nor the LPS-induced increase in pulmonary vascular permeability. The se results suggest that the mechanism of APC inhibition of LPS-induced pulmonary vascular injury was independent of its anticoagulant activi ty and was related to its ability to inhibit accumulation of leukocyte s. In addition, these findings suggest that the serine protease activi ty of APC may be essential to its inhibitory effect on LPS-induced pul monary accumulation of leukocytes and subsequent pulmonary vascular in jury. (C) 1996 by The American Society of Hematology.