The inability of the present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop newer, more effective interventions. In this respect, our studies, using a model of chronic polymicrobial septic mortality (i.e., cecal ligation [CL] and puncture [CLP]), indicate that it is the response to devitalized/injured tissue present in CLP that appears to predispose the host to the induction of a suppressive lymphoid and/or macrophage (M/phi) phenotype. Microbial stimuli, in turn, serve to induce the subsequent immune dysfunction (pro-inflammatory & Th1-function) as well as the mortality seen in CLP. We have shown that the production of IL-10, IL-4, TGF-beta and/or NO appear to contribute to the suppression of Th1/pro-inflammatory responsiveness seen in late sepsis in a tissue specific fashion via p38 MAPK, STAT-6, and/or SOCS proteins. In the spleen, this appears to be the result of Th2-cell differentiation. Conversely, preliminary studies indicate that gamma8 T-cells and/or CD8+-T-cells play a role in changes in the innate and not the cellular immune response to septic challenge. Alternatively, mice inhibited in their ability to activate an NK-T-cell response exhibit improved septic survival. In light of the above, this proposal will test the hypothesis that the immune hypo responsiveness, thought to predispose these animals to multi-organ failure and death as seen in sepsis, is the result of a dysfunctional response to infectious challenge in the presence of necrotic /injured tissue (CL). Further, this inability to appropriately respond to infectious/inflammatory stimuli is driven by concomitant development of regulatory lymphoid/M/phi phenotype(s) as a response to the tissue injury (CL). Utilizing specific gene deficiency or antibodies or inhibitors we will: (1) establish which T-cell/M/phi sub-populations contribute to the suppression of cellular/Th1 lymphoid responsiveness seen in the spleen, intestine and liver following CL or CLP; (2) we will determine the role of p38 MAPK, STAT6 and SOCS-3 in the development of these regulatory cell sub-populations; (3) we will establish the role of IL-10, IL-4, TGF-beta and NO (from iNOS) in the development of these regulatory cell sub-populations in the response to CL or CLP; and (4) we will establish to what extent these changes are a result of stimulation via pattern recognition receptors (toll-family receptors, TLR) and/or apoptotic cell recognition. It is our firm belief that the results of these studies will provide information that not only will allow us to better understand the pathobiology of sepsis-induced immune dysfunction, but also its attenuation.
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