The pathophysiological mechanisms of local microvascular injury as well as secondary organ injury following thermal skin burns are not well understood. Neutrophils and vascular endothelial cells, together with inflammatory mediators and adhesion molecules, appear to play an important role in these events. It appears that local (skin) and remote (lung) injury after thermal trauma results from a complex interplay of cytokines (TNFa, IL-1), adhesion molecules (endothelial and leukocytic), and the complement activation products. It is postulated that cytokines play a major role in upregulation of both leukocytic and endothelial adhesion molecules. In order to explore the roles of these molecules, the applicants will assess the extent to which cytokine blockade protects against skin and lung vascular injury after thermal trauma of skin, evaluate the roles of adhesion molecules, and determine if blocking of C5a is protective. Since cytokine release and complement activation occur after thermal trauma and products of both mediator systems can activate neutrophils, they will assess the upregulation of CD11b and CD18 and the down regulation of L-selectin on blood neutrophils, after thermal injury, as surrogates of intravascular activation of these cells. Protective interventions will be evaluated for their ability to prevent these changes reflective of intravascular activation of neutrophils. At the tissue level, they will monitor E- and P- selectins, and ICAM-1 in skin and lung tissue sections. The studies will also be extended to include human burn patients.
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