DIVERSE EFFECTS OF CHEMOKINES IN SYSTEMIC INFLAMMATION

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The clinical manifestation of sepsis and acute lung injury is often the consequence of cell interactions, resulting in excessive inflammatory mediator expression, leukocyte activation, and tissue injury. In spite of advances in the development of microbial antibiotics, biotechnology, and critical care management, morbidity and mortality due to sepsis related disorders has not significantly changed in the past 30 years. Clinically, the therapeutic options available to treat these disorders are limited, which reflects an insufficient understanding of the mechanisms that underlie these symptoms. Microbial organisms and the subsequent host's cytokine response have been identified as major etiologic factors that contribute to the initiation and perpetuation of multi-organ injury. Recent data supports the concept that cytokines and chemokines possess diverse activities during the development of systemic inflammation and acute lung injury. Thus, our studies directed at understanding mechanisms responsible for regulating the expression and activities of chemokines during the evolution of acute systemic inflammation are the broad, long- term objectives of this application. We hypothesize that established cytokine networksxp result in the expression of the chemokines MIP-2 and MCP-1 which can respectively exert inflammatory or immunoregulatory effects during the evolution of systemic inflammation. The proposed studies will focus on the following questions: 1) What is the contribution of MCP-1 and MIP-2 to the pathology of septicemia and acute lung injury? 2) What is the cellular and molecular mechanism whereby MCP-1 exerts an immunoregulatory effect on the evolution on the evolution of systemic inflammation and acute lung injury? 3) How does the immunomodulatory cytokine interleukin-10 (IL-10) diversely regulate the expression of MIP-2 and MCP-1? 4) How does the evolution of the septic response differ in MCP- 1 and CCR2b (MCP-1 receptor) knockout mice, as compared to wild-type mice? 5) Does the expression of MCP-1 during the development of sepsis in humans correlate with clinical disease? In this section, endotoxemia and cecal ligation/puncture-induced septicemia will be utilized to assess the contribution of MIP-2 and MCP-1 to evolving organ injury. Mechanisms for the regulation of MIP-2 and MCP-1 will be studied via bioassays, ELISAs, immuno-histochemistry, Northern blot or RT-PCR, in situ hybridization, mRNA stability and nuclear run-on analyses. The studies designed in this proposal will demonstrate that the chemokines MIP-2 and MCP-1 play diverse roles in mediating the pathogenesis of multi-organ injury.