EFFECTS OF VARIOUS DOSES OF ANTITHROMBIN-III ON ENDOTOXIN-INDUCED ENDOTHELIAL-CELL INJURY AND COAGULATION ABNORMALITIES IN RATS

We previously demonstrated that antithrombin III reduced the injury to endothelial cells caused by activated leukocytes in rats administered endotoxin. This occurred via the increase of the endothelial release of prostaglandin I-2, which is a potent inhibitor of leukocyte activat ion. We evaluated the dose of antithrombin III required to prevent suc h endothelial cell injury in rats administered endotoxin, by comparing the effects of various antithrombin III doses on the pulmonary vascul ar injury. The intravenous administration of endotoxin, 5 mg/kg, produ ced a transient accumulation of leukocytes in the lung, followed by pu lmonary vascular injury, as indicated by an increase in the pulmonary vascular permeability, and coagulation abnormalities. The dose of 250 U/kg significantly inhibited all such effects of endotoxin, While lowe r doses of antithrombin III (50 and 100 U/kg) significantly inhibited such coagulation abnormalities, they failed to prevent either the pulm onary accumulation of leukocytes or the subsequent pulmonary vascular injury. Rats administered endotoxin exhibited an accumulation of neutr ophils and edematous changes in the pulmonary interstitial space. Alth ough such changes were reduced after 250 U/kg of antithrombin III, the y were unaffected by lower doses of 50 and 100 U/kg. Plasma levels of 6-keto-PGF(1) alpha were markedly increased in rats 90 min after the a dministration of endotoxin, and were significantly decreased in the en dotoxin-treated rats administered the lower doses of antithrombin III (50 and 100 U/kg), but not altered in those endotoxin-treated rats rec eiving 250 U/kg of antithrombin III. These findings suggest that a hig her antithrombin III dose is necessary to prevent endothelial cell inj ury than is required to inhibit coagulation abnormalities in an animal model of sepsis, These observations support the notion that antithrom bin III may prevent endotoxin-induced endothelial cell injury by promo ting endothelial release of prostaglandin It and thus inhibiting leuko cyte activation. (C) 1998 Elsevier Science Ltd.