ATTENUATION OF ENDOTOXIN-INDUCED PULMONARY VASCULAR INJURY BY ANTITHROMBIN-III

We evaluated the effects of antithrombin III (AT III) on the pulmonary vascular injury induced by injecting rats with lipopolysaccharide (LP S) to investigate the possible usefulness of AT III as a treatment for acute respiratory distress syndrome. The intravenous administration o f AT III prevented the pulmonary accumulation of leukocytes (as evalua ted by myeloperoxidase activity) and the increase in pulmonary vascula r permeability to I-125-bovine serum albumin induced by LPS. The incre ase in pulmonary vascular permeability induced by LPS administration w as unaffected by various anticoagulants but was inhibited by the leuko cytopenia induced by nitrogen mustard or by the administration of a gr anulocyte elastase inhibitor, ONO-5046. AT III given alone, but not he parin plus AT III or Trp(49)-modified AT III, which lacks affinity for heparin, significantly increased the plasma concentration of 6-keto-p rostaglandin F-1 alpha, suggesting that the interaction of AT III with heparin-like substances at the endothelial cell surface promotes the release of prostacyclin from endothelial cells in vivo. Trp(49)-modifi ed AT III failed to prevent the LPS-induced accumulation of leukocytes and vascular injury. The pulmonary accumulation of leukocytes and vas cular injury induced by LPS were not prevented by administering AT III to rats that were pretreated with indomethacin. The continuous intrav enous infusion of prostacyclin prevented the LPS-induced pulmonary acc umulation of leukocytes and vascular injury. Findings suggest that AT III depends on its ability to promote the release of prostacyclin, a p otent inhibitor of leukocyte activation, from endothelial cells to pre vent pulmonary vascular injury induced by LPS.