PATHOPHYSIOLOGICAL BIOCHEMICAL CHANGES OF THERMAL INJURY

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DESCRIPTION (provided by applicant): Previous studies suggested that signaling through Toll/IL-1 pathway plays a role in organ responses to burn trauma. This application will extend these studies, addressing the hypothesis that Toll/IL-1 pathway is an injury response system which senses injury other than infection; a primary function of this pathway is to detect/limit local injury. Studies will examine the hypothesis that burn injury produces an initial insult resembling infection, which in turn, increases susceptibility to sepsis. Specific Aim 1 examines the hypothesis that burn injury produces an infectious-like injury related to loss of gut barrier function/translocation of endotoxin/bacteria, providing one proximal signal that triggers postburn innate host response; effects of selective decontamination of the digestive tract on postburn responses to subsequent sepsis (IT Streptococcus or Klebsiella pneumoniae) will be examined. Specific Aim 2 examines contribution of Toll/IL-1 signaling in immune cells to postburn cardiac responses. Using adoptive transfer between histocompatible mouse strains, we will generate TLR4 chimeras: TLR4 deficient mice with TLR4 +/+ immune systems or TLR4 +/+ animals lacking TLR4 in hematopoietic cells. Specific Aim 3 examines the hypothesis that cardiomyocyte-specific Toll/IL-1 signaling plays a role in myocardial inflammation/dysfunction after burn trauma. A transgenic approach will allow reconstitution of TLR4-mediated signaling in cardiomyocytes of TLR4 deficient mice. Specific Aim 4 will determine if CD14 signaling is required forTLR4 activity in burn-related myocardial inflammation/dysfunction. Whether CD14 activity is a pre-requisite for Toll/IL-1 signaling after burn trauma will be examined in CD14 knockout mice given burn (or sham burn) injury and in CD14 knockout burns given soluble CD14 to reestablish CD14/TLR4 signaling. Specific Aim 5 will examine the hypothesis that the degree of myocardial inflammation/injury/dysfunction after burn injury predict susceptibility to infection/sepsis. Echocardiography, serum troponin, and heart rate variability measured in rats and man (Human Core) will determine if these measures identify subjects at increased risk for sepsis. These studies should identify extracellular signals which activate signal transduction pathways leading to burn/sepsis related inflammation/dysfunction, allow development of therapeutic strategies providing cardioprotection, not only for victims of burn trauma but also for patient populations in whom cardiac dysfunction contributes to increased mortality.