Thermal injury is a form of physical trauma which, depending upon its severity, results in widespread changes to many metabolic and physiologic systems. In extreme situations, or when additional complications arise, the consequences of thermal injury are lethal. Continued improvements in the clinical programs used to treat burned individuals have significantly improved the probability of surviving the trauma associated with severe burn. However, early successes can be rapidly reversed if the burn patient acquires a bacterial or viral infection. Enhanced susceptibility to infectious diseases, therefore, represents an important area of concern in the clinical management of burn patients since their immunologic defense mechanisms are generally depressed. The T lymphocyte, particularly its capacity to respond normally to antigenic insults and produce those lymphokines essential to the development of protective immune responses (e.g., IL-2 and gammaIFN), represents a keystone in the alterations in immune function which are associated with thermal injury. Employing a murine thermal injury model, we plan to elucidate the responsible mechanisms, and utilize appropriate therapies to reverse or eliminate those factors responsible for causing the immunologic alterations. Our experimental plan has four main objectives. First, we will evaluate whether burn-mediated effects on T cells in vivo progress anatomically (from being localized to systemic) depending upon the extent of thermal injury. Second, we will question the extent to which T cells are being compromised by: a) alterations to their functional transmembrane signaling pathways, b) influences caused by elevated glucocorticoid levels, or c) depressions in their capacity to effectively utilize DHEA for transcriptional enhancement of their IL-2 and gammaIFN genes. Third, treatment protocols will be instituted in thermally injured mice to inhibit PGE production, inhibit GCS function, or promote DHEA activities, followed by careful assessments of immune function. Fourth, those treatments or combination of treatments which prove clinically beneficial will be tested for efficacy in bacterial translocation, infectious challenge, and age-associated susceptibility to thermal injury models.
