The activation of a pro-inflammatory cascade after bum injury appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. Macrophages (Mphi) are major producers of pro-inflammatory mediators with increased productive capacity being observed post-burn. Thus, Mphi hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) may be of critical importance in the development of these complications. Nonetheless, the mechanisms responsible for the alterations in M? activity are unclear. We have utilized a murine scald burn model (3rd degree, 25% total body surface area) and our preliminary results indicated that at 4-7 days post-burn Mphi were """"""""hyperactive"""""""" (increased productive capacity for nitric oxide, TNF-alpha, IL-6 and PGE2), T cell function is suppressed and increased susceptibility to sepsis exists. We have observed significant mortality (approximately 75%) during the initial 48 hr. post-burn period in mice lacking gamma/delta T cells (gamma/delta T cell knock-out mice) and M? isolated from surviving mice at 7 days post-burn appear not to be """"""""hyperactive"""""""". These findings suggest a dual role for ?/? T cells in burn injury pathogenesis; 1) survival early and; 2) induction of M? hyperactivity later. The expression of M? hyperactivity post-burn appears to be related to altered sensitivity to cAMP, however, the mediators and mechanisms responsible for Mphi hyperactivity and immune dysfunction post-burn are unknown. Moreover, it is unclear whether changes in fixed tissue immune cell function post-burn correlate with changes in peripheral blood mononuclear cell (PBMC) function, which is assessed clinically. It is our hypothesis that Mphi hyperactivity post-burn is mediated by gamma/delta T cells and altered cAMP responses leading to the development of immune dysfunction. We propose to determine the following: 1) The relationship between gamma/delta T cells, Mphi band survival early (initial 48 hr.) post-burn; 2) The role of ?/? T cells in the induction of M? hyperactivity late (7 days) post-burn; 3) The mechanisms responsible for M? hyperactivity post-burn; and 4) The effect of burn injury on PBMC function. A more comprehensive understanding of the relationship between M? activity, T cell function, and immune dysfunction after thermal injury should hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients. The long term goals of the applicant's research are to determine the mediators and mechanisms responsible for immune dysfunction after thermal injury. This award along with the excellent environment in the Center for Surgical Research for conducting these studies will significantly facilitate the applicant's further development as an Independent Investigator.
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