BIOCHEMISTRY OF TRAUMA-INDUCED INFLAMMATION

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1. Models of inflammation in rabbits and rhesus monkeys have indicated that stimulation by bacterial lipopolysaccharide (LPS) by the intravenous route induces accumulation of leukocytes on the luminal surface of pulmonary blood vessel, without emigration into the extravascular and alveolar spaces and without demonstrable tissue injury. By contrast, intrabronchial stimulation with LPS induces emigration of leukocytes and damage, and is associated with generation of TNF, IL-1, IL-8 and IL-6 in the lung. These cytokines are not found in the lung tissues after intravenous stimulation with LPS. We propose to determine if inhibition of these cytokines modifies the sequential appearance of cytokines, leukocytic emigration and pathophysiologic changes in the lung. The receptor-binding domain of IL-8 has been tentatively identified, and antibodies to this domain will be employed to assess the importance of IL-8 in LPS-induced leukocytic emigration. The domain of the extracellular hydrophilic region of the hepatic IL-6 receptor, responsible for binding the signal-transducing component, GP-130, will be identified, and antibodies prepared to it. These antibodies will be used to block IL-6 in hepatocytes of the acute phase protein, LPS-binding protein (LBP). LBP may participate in the appearance of the hyper-responsive state exhibited by rabbits to LPS that develops over a 24 hour period. Inhibition of the IL-6 receptor may modify not only LBP formation, but the hyper-responsive state. 2. Experiments will be continued on the role of leukocytic oxidants in inflammatory injury. Studies to date have defined specific changes in cells exposed to leukocytic oxidants that will help significantly in studying the effect of oxidant inhibition.