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

We have reported recently that lipopolysaccharide endotoxin and platelet 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 findings highly reminiscent of the adult respiratory distress syndrome. The present study was designed to examine the role of TNFalpha in lipopolysaccharide/platelet activating factor-induced lung injury by utilizing a highly specific monoclonal antibody which block TNFalpha actions (anti-TNFalpha monoclonal antibody). Pretreatment with anti-TNFalpha monoclonal antibody (2.5-25 mg/kg i.v., n = 5-9) dose-dependently prevented the lipopolysaccharide/platelet activating factor-induced histopathological changes, lung edema (P < .01), lung myeloperoxidase activity (P < .01), elevation of neutrophil count in bronchoalveolar lavage fluid (P < .01) and increased serum thromboxane B2 (P < .01). Indomethacin (6 mg/kg i.v., n = 5) failed to modify the lung injury despite complete inhibition of thromboxane B2 formation (P < .05). These data suggest that TNFalpha might play a key role in initiation of the early inflammatory changes which lead to adult respiratory distress syndrome.