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 superior therapeutic interventions can be designed. Studies suggest that the majority of the deleterious effects in sepsis are due to endotoxin (ET) stimulation of macrophage to release various harmful mediators. However, few studies have been carried out in animal models which mimic the clinical state of sepsis. Our studies indicate that polymicrobial sepsis, produced by cecal ligation and puncture (CLP) in either ET-tolerant or ET-intolerant mice, produces: 1) early (1 h) in vivo activation of peritoneal microphage, but not alveolar microphage cytokine release, implying that sepsis, unlike ET, may differentially affect various microphage populations; 2) early circulating ET levels of < 0.01 microgram/Kg BW (~1000X below the levels typically administered to induce a shock-like state); 3) elevated levels of inflammatory mediators (IL-1, IL-6, TNF, PGE2) in the blood of mice; 4) similar mortality rates. Therefore, we postulate that ET is not the primary mediator of altered microphage function during polymicrobial sepsis. While ET can induce inflammatory agent release when administered in vivo at 1000X higher doses, we hypothesize that the levels of ET present early (1-12 h) in sepsis are insufficient to induce these changes in microphage function. We propose studies to determine: 1) how sepsis, as opposed to chronic low dose ET infusion, alters the functions of microphage from the peritoneum, lungs, liver and spleen; 2) whether or not the effects of microphage stimulation by microbes released during sepsis initiates a series of irreversible events. To determine this, the septic focus will be removed in the early or late stage of sepsis and the effects on microphage function will be assessed; 3) to what extent microphage from the liver or spleen of septic or chronic low dose ET infused mice alter hepatocyte or lymphocyte functional capacities; 4) whether or not agents known to block microphage mediator release can ameliorate changes in microphage function initiated by sepsis. A clear understanding of the mechanisms underlying the pathophysiology of sepsis should provide a basis from which to develop more clinically relevant therapies.
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