TUMOR-NECROSIS-FACTOR-ALPHA MEDIATES ENDOTOXIN-INDUCED LUNG INJURY INPLATELET-ACTIVATING FACTOR-PRIMED RATS

We have reported recently that lipopolysaccharide endotoxin and platel et activating factor cooperate in priming relationships to elicit lung microvascular injury. Lung injury was associated with elevated serum levels of tumor necrosis factor-alpha (TNFalpha) and histological find ings highly reminiscent of the adult respiratory distress syndrome. Th e present study was designed to examine the role of TNFalpha in lipopo lysaccharide/platelet activating factor-induced lung injury by utilizi ng a highly specific monoclonal antibody which block TNFalpha actions (anti-TNFalpha monoclonal antibody). Pretreatment with anti-TNFalpha m onoclonal antibody (2.5-25 mg/kg i.v., n = 5-9) dose-dependently preve nted the lipopolysaccharide/platelet activating factor-induced histopa thological changes, lung edema (P < .01), lung myeloperoxidase activit y (P < .01), elevation of neutrophil count in bronchoalveolar lavage f luid (P < .01) and increased serum thromboxane B2 (P < .01). Indometha cin (6 mg/kg i.v., n = 5) failed to modify the lung injury despite com plete inhibition of thromboxane B2 formation (P < .05). These data sug gest that TNFalpha might play a key role in initiation of the early in flammatory changes which lead to adult respiratory distress syndrome.