The early events of severe sepsis and acute lung injury set in motion a cascade of mechanisms which significantly contribute to the morbidity and mortality observed during the first few days of this syndrome. While sepsis has often been viewed as a deadly acute disease, survivors also suffer long-term consequences. Clinical data underscores the enigma of subsequent high mortality rates associated with patients who are long-term survivors of the acute septic episode. For example, within one year of surviving severe sepsis, there is a 26% predicted mortality rate, with many patients succumbing to lung complications. In this renewal application we will expand upon our previous investigations and focus on the cellular and molecular mechanisms which dictate the longer-term sequela of sepsis and related lung injury. We have established a model of experimental sepsis (cecal ligation and puncture-CLP) which results in an approximate 60% survival rate. Our preliminary studies have demonstrated that these survivors are susceptible to either a fungal or bacterial infection with 100% mortality when challenged 2-3 weeks post recovery from the initial CLP; with changes in cytokine and toll-like receptor (TLR) expression and alterations in lung leukocyte populations. No challenged sham control animals died. We hypothesize that the lung becomes uniquely predisposed to infection for extended periods of time after animals survive severe sepsis via mechanisms that include alterations in the inflammatory cytokines IL-12 and IL13, an increase in immunoregulatory chemokines MCP-1 and C10, and alterations in innate immunity. Our studies will focus on the following Specific Aims: To compare and contrast mediators, TLR, and lung immune cells in models of long-term survivors of mild and severe sepsis, as these animals respond to a subsequent challenge. To investigate the mechanisms by which IL-12 and IL-13 contribute to innate immunity after pathogen challenge of surviving septic animals by influencing cytokine expression profiles, TLR expression, and lung leukocyte elicitation and activation. To assess the mechanistic contribution of CC chemokine with unique immunoregulatory activity to the long term modulation of the lung post severe sepsis. To determine the contribution of lung resident, structural cells as they participate in the innate response of long-term sepsis survivors to a pathogen challenge. Our long term goals are to demonstrate the mechanistic contributions of cytokines, TLR, and dendritic cells to the long term problems of severe sepsis and acute lung injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-3 (02))
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Harabin, Andrea L
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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