Dynamic Effects of Chemokines on Systematic inflammation

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The initation and maintenance of sepsis and acute lung injury are dependent upon a diverse collection of ill-understood cellular and molecular mechanisms, which are likely triggered as a result of an overwhelmed or failed innate immune response and a subsequent cytokine storm. These processes set in motion a cascade of events which significantly contribute to the pathology of this syndrome, including altered physiology, immunosuppression, and impaired healing. Our preliminary data support the concept that during experimental sepsis CCR4 andTARC/CCL17(Thymus and activated-regulated chemokine), possess novel biological activities on both the innate immune response and subsequent down-stream immune systems. Based on these data, we hypothesize that TARC:CCR4 expression, by structural resident cells and leukocytes, respectively, are key regulatory components of the septic response. This mechanistically occurs by modulating early cytokine expression, toll-like receptor (TLR) expression and leukocyte activation and elicitation. The expression of CCR4 and TARC during these initial responses have profound effects on subsequent sepsis pathology. Our studies will focus on the following Specific Aims: 1) to investigate the time-course, magnitude of expression, and cellular sources of CCR4 and TARC during the evolution of experimental sepsis; 2) to determine the mechanistic role by which TARC and CCR4 expression can regulate the progression of experimental sepsis by influencing specific cytokine expression profiles, leukocyte activation and elicitation, and TLR expression; 3) to assess the contribution of resident, structural cell-derived TARC in regulating the innate and subsequent systemic inflammatory response in experimental sepsis; and 4) to investigate the expression of CCR4 and TARC by cells and fluids recovered from patients with clinically defined sepsis and correlate the expression patterns with characterized phases of disease. A number of important tools will be used in this application to determine the cellular and molecular mechanism(s) of TARC:CCR4 induced regulation, including the use of CCR4-/- mice. Both experimental systems of sepsis and clinical specimens will be used to achieve our long term objective, which is to demonstrate the important mechanistic contribution of chemokine receptors and their ligands to the evolving immune response and how these interactions impact on the various phases of sepsis.