Despite the use of specific antibiotics, aggressive operative intervention, and the nutritional support of trauma patients, sepsis and multiple organ failure continue to be a major problem in the surgical intensive care units. Thus, it is essential to determine the mechanism underlying the pathophysiology of sepsis so that more appropriate therapeutic interventions can be designed. Experimental studies indicate that polymicrobial sepsis induces a marked suppression in both lymphocytic and macrophage function which correlates with decreased survival. These changes are associated with decreased cellular ATP levels and increased cellular Ca+2 load. However, such alterations are not evident until late (>12 h) following the onset of sepsis, suggesting this is a time dependent process. Alternatively, early in sepsis, (0-4 h), macrophage from the liver and peritoneum secrete elevated amounts of proinflammatory cytokines associated with the systemic release of these agents. Furthermore, we have been able to detect sustained elevated release of immunosuppressive agents, TGF-beta, IL-4, IL-l0, PGE2 and glucocorticoids, following the induction of sepsis. Inasmuch, investigators have suggested that an inflammatory agent(s) may be responsible for this marked suppression of immune cell function. Interestingly, several laboratories examining the in vitro effects of these mediators on various immune cells have reported that many of these same agents have the capacity to induce a process referred to as programmed cell death (PCD). PCD is dependent on the de novo synthesis of specific genes which initiate a time dependent cellular suicide program in response to stimuli, as opposed to necrotic cell death. Recently, we have obtained evidence of this process in immune cells after the onset of sepsis. Preliminary data also suggests that changes in the rate of PCD in blood leukocytes may be diagnostic of the septic animals hypodynamic/circulatory state. It is our hypothesis that the induction of PCD (and not necrotic cell death) contributes to immune cell hyporesponsiveness seen during sepsis. We, therefore, propose to determine; l) whether or not polymicrobial sepsis alters the rate of PCD in not only hematopoietic tissue, such as the thymus and bone marrow, but also in unstimulated T-/B-lymphocytes, monocyte/macrophage and myeloid cell populations in the spleen, blood, liver, peritoneum, lungs and lymph nodes; 2) whether the inability of T-/B-lymphocytes and macrophages to respond to non-specific mitogens (immunocompetance) isolated from septic animals is due to the onset of accelerated PCD; 3) which mediator(s) released during the systemic inflammatory response to polymicrobial sepsis contribute to changes observed in immune cell PCD; 4) if liver damage associated with polymicrobial sepsis is due to increased PCD in hepatocytes and if this is due to the release of mediators by the activated Kupffer cells during early sepsis; and S) the extent to which prior exposure to shock alters the functional response of mice to polymicrobial subsequent septic challenge. A clear understanding of the mechanisms underlying the pathophysiology of sepsis, and PCD's contribution to it, should provide a basis from which to develop not only more effective therapy, but also potentially better monitoring of the inflammatory status of the septic patient.
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