A NOVEL PLATELET-ACTIVATING-FACTOR ANTAGONIST, SM-12502, ATTENUATES ENDOTOXIN-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION AND ACUTE PULMONARY VASCULAR INJURY BY INHIBITING TNF PRODUCTION IN RATS

Adult respiratory distress syndrome and disseminated intravascular coa gulation are important pathologic conditions affecting the outcome of patients with sepsis. To elucidate the possible therapeutic efficacy o f SM-12502, a novel platelet activating factor antagonist, on acute lu ng injury and disseminated intravascular coagulation in sepsis? we inv estigated the effect of SM-12502 on an endotoxin (ET)-induced septic m odel in rats. SM-12502 prevented ET-induced increases in pulmonary vas cular permeability and ET-induced histologic changes, such as leukocyt e infiltration and pulmonary interstitial edema, 6 h following the adm inistration of ET (5 mg/kg). SM-12502 also inhibited the decrease in f ibrinogen and the increase in fibrin and fibrinogen degradation produc ts observed following ET administration. SM-12502 prevented increases in the serum concentration of tumor necrosis factor (TNF) 90 min follo wing ET administration in vivo, and significantly inhibited the produc tion of TNF-alpha by ET-stimulated monocytes in vitro. These findings suggest that SM-12502 attenuates the actions of endotoxin by the inhib ition of TNF production.