IMMUNOMODULATION OF MACROPHAGES FOLLOWING TRAUMA

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Alterations in macrophage function following trauma contribute both to an enhanced susceptibility to infection and sepsis, and to the pathogenesis of multiple organ dysfunction and failure, particularly adult respiratory distress syndrome (ARDS). Paradoxically, both enhancement of the macrophage immunoinflammatory response to correct post injury defects and suppression of a systemic macrophage immunoinflammatory response, following severe trauma and sepsis, have been advocated as therapy in the critically ill patient at risk for ARDS. The long term goals of the present proposal are to further elucidate the cellular mechanisms involved in the immunomodulation of the alveolar macrophage following trauma in order to better define and direct therapy in the patient at risk. Hypothesis: Metabolism of the alveolar macrophage membrane lipid arachidonic acid produces extracellular mediators of inflammation and major intracellular second messengers that modulate the macrophage immunoinflammatory response. This intracellular system modulates the macrophage response to stimulation by 1.) inflammatory mediators, such as endotoxin and macrophage inflammatory peptides. 2.) immunomodulation by priming (gamma interferon and platelet activating factor) and suppressive (non-steroidal anti-inflammatory drugs and lazaroids) agents, and 3.) autocroid augmentation of macrophage function by macrophage generated inflammatory mediators (tumor necrosis factor and platelet activating factor). To test this hypothesis the following specific aims will be pursued: 1.) Arachidonic acid metabolites involved in signal transduction during inflammatory stimulation of the macrophage will be identified. 2.) The interaction of arachidonic acid metabolites with the phosphoinositol signal transduction pathway following macrophage stimulation will be investigated. 3.) The effect of immunomodulators on arachidonic acid metabolism and subsequent inflammatory mediator production by control and stimulated macrophages will be elucidated. 4.) Involvement of arachidonic acid in signal transduction of macrophage products functioning as autocrine self- augmenting mediators will be delineated. 5.) The effect of alterations in arachidonic acid metabolism on the pathophysiologic response to macrophage stimulation will be investigated in vivo in a rabbit model. 6.) Determination of similar cellular mechanisms in the human system will be studied utilizing circulating and bronchoalveolar lavage alveolar macrophages from normal volunteers and patients with ARDS. The elucidation of the cellular mechanisms involved in the up- and down- regulation of macrophage function in the post injury state and the subsequent response to inflammatory mediators will help direct the development of appropriate safe therapeutic interventions.