IMMUNODULATION OF MACROPHAGE FOLLOWING TRAUMA

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Trauma remains a major cause of death and disability in America, and, the number one cause of mortality in the one to forty-five year old age group and for loss of productive years of life overall. In turn, the major cause of late death following trauma is organ dysfunction, including ARDS, leading to multiple organ failure syndrome (MOFS) and death. The primary etiology of ARDS and MOFS is the clinical "sepsis syndrome" or systemic inflammatory response syndrome (SIRS) causing disseminated tissue injury and organ dysfunction. The long lived, highly diverse tissue-fixed macrophage is a crucial central coordinator of both the normal and aberrant host immunoinflammatory response and is responsible for the induction and persistence of the "malignant systemic inflammatory response" seen in MOFS. The macrophage is both "primed" and activated by a multitude of stimuli in the inflammatory milieu. Until now therapeutic approaches have focused on control or inhibition of single components of the overall inflammatory response. However, since the inflammatory response is so replete with redundance and feedback amplification mechanisms, it is appealing to broaden our focus to more generally control the inflammatory injury. To achieve this goal, we propose to better define the cellular mechanisms of macrophage activation and develop therapeutic interventions based on modulation of the over-aggressive macrophage immunoinflammatory response. Hypothesis: The aberrant macrophage inflammatory response can be modulated by manipulation of cellular signal transduction mechanisms that control inflammatory mediator genes. Elucidation and control of these macrophage cellular mechanisms will permit development of safe therapeutic interventions to potentially prevent ARDS, MOFS and death. To test this hypothesis the following specific aims will be pursued: l.) delineate and confirm the proposed components of the macrophage-LPS signal transduction pathway, 2.) elucidate the molecular mechanisms of "priming" (reprogramming) and/or autocrine augmentation of the macrophage response, 3.) determine the feasibility and effects of selectively modifying binding and uptake of LPS by stimulatory (CD14) and non-stimulatory (scavenger, acyl-LDL) receptors 4.) investigate the contribution of phospholipid metabolism to macrophage activation, 5.) evaluate the calcium-calmodulin (Ca-CaM) pathway in macrophage activation, and 6.) test the ability of antioxidants to alter inflammatory stimulus-signal transduction in the macrophage. Elucidation of the mechanisms controlling the macrophage response to inflammatory stimuli will permit development of therapeutic interventions to beneficially modulate the excessive macrophage and the subsequent host auto-destructive responses.