The early events of severe sepsis set in motion a cascade of mechanisms, which significantly contribute to both the acute and chronic morbidity and mortality associated with this syndrome. While sepsis has often been viewed as a deadly acute disease, it also has insidious long-term consequences. Clinical data underscores the high mortality rates associated with patients who are long-term survivors of the acute septic episode. Within eight years of surviving severe sepsis, there is an 80% predicted mortality rate, with many patients succumbing to cancer and inflammatory lung complications. In this revised, renewal application we will expand our previous investigations of acute systemic disease and focus on the cellular and molecular mechanisms which cause sepsis-induced long-term immune dysregulation. We have established an experimental model of severe sepsis (cecal ligation and puncture-CLP) which results in a long-term survival rate of approximately 60%. Our preliminary studies have demonstrated that these CLP survivors are susceptible to an innocuous microbe challenge with high mortality weeks after recovery, while 100% of the sham animals survive. The mechanism for the lingering susceptibility appears related to the initial depletion of DC populations and the subsequent "re-seeding" of tissue by impaired DCs that have undergone epigenetic changes, altering cytokine expression. We hypothesize that the long-term consequences of severe sepsis are caused by altered dendritic cell populations, as innate and acquired immune functions of re-seeded bone marrow-derived dendritic cells are modified via novel mechanisms, including epigenetic modifications, contributing to the altered immune functions that follows severe sepsis. Our studies will focus on the following Specific Aims: 1) To identify the contribution of dendritic cell subsets to the general pathology, cytokine expression, and alterations in immune cell function in long-term survivors of mild (90% survivors) and severe (50-60% survivors) experimental sepsis. 2) To determine the mechanism(s) responsible for the immunoregulation found in long-term survivors of severe sepsis by assessing novel mechanisms, including epigenetic modifications, that affect the expression of key immune cell-derived cytokine genes, and 3) To develop efficacious therapies to restore dendritic cell function after severe sepsis via adoptive cell transfer strategies and the pharmacologic targeting of epigenetic alterations.
Sepsis is a severe, life threatening disease that can affect multiple organs in the body. This disease is usually described as an acute disorder, but recent clinical studies have shown that there are medical consequences, which last for years after patients are released from the intensive care unit. We have experimentally modeled the long-term effects of severe sepsis and have uncovered important mechanisms that lead to impaired immune cell function associated with the chronic aspect of this disease.
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