NEURO MICROVASCULAR MECHANISMS IN SKIN INFLAMMATION

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DESCRIPTION: (Adapted from the applicant's abstract) The long-term objective of this application is to define the mechanisms responsible for the initiation and termination of cutaneous neurogenic inflammation, and to determine if defects in these processes result in dysregulated inflammatory responses in skin. The key hypotheses to be tested are: (1) That the neurological system may modulate inflammation in skin by releasing neuropeptides (e.g., substance P (SP)) that are capable of directly acting on the dermal microvasculature to mediate plasma extravasation, endothelial cell adhesion molecule expression, endothelial gap formation, and neutrophil infiltration, and (2) that these pro-inflammatory activities are attenuated by specific cell-surface proteases and by the desensitization of the respective neuropeptide receptor on the target endothelial cells. There are three specific aims. First is to characterize the interaction of SP with receptors on dermal microvascular endothelial cells (DMEC) and the spectrum of pro-inflammatory processes mediated by DMEC as a result of this neuropeptide stimulation. Second is to examine the cellular mechanisms responsible for regulating DMEC-mediated neurogenic inflammatory processes. Third is to determine the role of DMEC-mediated neurogenic inflammation in the pathogenesis of animal models of allergic contact dermatitis, irritant dermatitis, and acute photodermatitis.