MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS

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DESCRIPTION (provided by applicant): Despite continued improvements in early fluid resuscitation from burn trauma, early excision and grafting, and the use of both local and systemic antimicrobials to control wound infection, burn-related loss of the dermis poses a significant risk for infection in the burn patient. Inhalation injury, intubation and the need for prolonged ventilation contribute to a significant incidence of pneumonia that often progresses to multiple organ failure, a syndrome that carries a mortality rate of 50%. A persistent clinical concern is that the development of sepsis after burn trauma may exacerbate inflammatory responses and organ dysfunction associated with the initial injury. Numerous studies describe myocardial dysfunction in trauma and sepsis, but the precise cellular mechanisms remain unclear. One common feature of myocardial depression is the accumulation of cytosolic calcium ([Ca2+]i) by cardiomyocytes. Time course studies during the previous funding period confirmed that burn- or sepsis-related myocyte accumulation of Na+ precedes the rise in cellular Ca2+, suggesting that cardiomyocyte accumulation of Na+ may be a prerequisite for myocyte Ca2+ overload. The studies proposed herein will examine the overall hypothesis that Na+ accumulation by the cardiomyocytes is an initial event after burn trauma or sepsis and occurs via a PKC dependent pathway; Na+ loading, in turn, promotes myocyte Ca2+ loading; myocyte Ca2+ dyshomeostasis persists due to altered expression and function of specific Ca2+ transport proteins, i.e., alterations in Na+-Ca2+ exchanger and SERCA may decrease Ca2+ efflux from the myocytes. Mitochondrial and nuclear Ca2+ accumulation contribute to injury of these cellular organelles, producing free radical generation, altered DNA content and integrity, myocyte apoptosis and myocardial dysfunction. We further hypothesize that recovery from burn or sepsis-related myocardial injury and dysfunction is related to DNA excisional repair as well as myocyte replication. The proposed work focuses on five specific aims to increase our understanding of the cellular events involved in burn and sepsis-related myocardial injury.