Burn injury carries a disproportionately high morbidity and mortality in the elderly. Aging is associated with a significant shift in cytokines, among which increased interleukin (IL)-6 production has been best characterized. We hypothesize that overproduction of IL-6 associated with aging predisposes the elderly to myocardial depression after burn injury and sepsis. Particularly, IL-6 overproduction by cardiomyocytes plays an important role in cardiac contractile dysfunction after burn injury complicated by sepsis, serving as the initiating event in causing multiorgan dysfunction and the resultant increase in morbidity and mortality in elderly burn victims. In the proposal, we will use our established model of 40% TBSA burn followed by S. pneumoniae sepsis in mice to address the following Specific Aims: 1). To determine the changes in both systemic and cardiomyocyte secretory profiles of IL-6 associated with aging: we will examine IL-6 levels in peripheral blood as well as IL-6 secretion by cardiomyocytes in mice at various ages (from 2 to 24 months). 2). To determine age-related changes in cardiac contractile function and correlate it with IL-6 secretion by cardiomyocytes in old wild type mice and young mice overexpressing myocardial IL-6.3). To determine if exaggerated IL-6 responses to burn, sepsis, and burn complicated by sepsis exacerbates the cardiac contractile dysfunction in old mice. 4). To confirm the role of excessive IL-6 in the predisposition of old burn and septic subjects to exaggerated cardiac contractile dysfunction and worsens outcome, we will use IL-6 knockout mice as well as IL-6 and IL-6 receptor antibody treatment in old mice to evaluate their cardiac contractile function, organ perfusion and function, and survival. The current proposal also serves as a career development award for the applicant towards as an independent and multidisciplinary investigator in the area of burn, sepsis, and geriatric critical care. The proposal will allow the principal investigator to generate data to address the Specific Aims and to allow didactic training necessary for his career development.
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