Thermal injury represents a common form of trauma associated with significant mortality and morbidity. Despite the remarkable improvements in critical care and wound management, end-organ effects of systemic inflammatory reactions characteristic of multiple organ edema and dysfunction remain life-threatening problems in patients with major burns. Of great concern is the development of microvascular barrier dysfunction, a fundamental cellular process underlying inflammatory edema that has yet to be understood at the molecular level. The overall goal of this project is to identify key signaling molecules and structural components responsible for the microvascular hyperpermeability response to thermal trauma. Within this context, a major hypothesis is developed stating that Src tyrosine kinase-signaled endothelial cytoskeletal contraction and junctional disorganization induce microvascular barrier dysfunction during thermal injury. Correspondingly, four specific aims will be achieved: 1) to characterize burn-induced microvascular leakage; 2) to examine the mechanism by which endothelial cytoskeletal contraction causes microvascular hyperpermeability; 3) to elucidate the role of VE-cadherin junctional disorganization in mediating endothelial barrier dysfunction; and 4) to verify the common signaling role of Src in the regulation of cytoskeletal and junctional structure and function. The study will test the hypotheses using a clinically relevant rat model of scald burn in combination with pharmacological approaches and molecular biology techniques. The study will provide new insights into the cellular and molecular control of endothelial barrier function. Information derived from this study will enhance our knowledge on microvascular pathobiology of not only burns but also other types of injuries associated with inflammatory responses. Furthermore, identification of signaling or structural molecules directly responsible for microvascular hyperpermeability should lead to the development of new therapeutic targets specific to the injurious process.
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