The long term goals of this project are to elucidate the mechanisms of immune dysfunction that occur after thermal injury. There is increasing evidence that the stress hormones and neurotransmitters, such as the endorphins and enkephlins, may represent an information channel between the immune, endocrine, and central nervous systems. Thus, the first aim is to investigate whether the burn-stress induced changes in hormone levels and endogenous opiates result in impaired neutrophil and/or lymphocyte function. To accomplish this aim, the in vitro effect of the stress hormones and endogenous opiates on neutrophil (bactericidal activity, and chemotaxis) and lymphocyte function (spontaneous and mitogen stimulated blastogenesis) will be determined and correlated with hormonally-mediated changes in neutrophil (cyclic nucleotides, oxygen consumption, energy charge) and lymphocyte metabolism (cyclic nucleotides, energy charge). The results of these studies, using leukocytes from healthy volunteers, will serve as the background against which to compare the spontaneously acquired defects in leukocyte function and metabolism that occur after thermal injury.
The second aim i s to investigate possible mechanism(s) responsible for the prognostically important functional defects in neutrophil and lymphocyte function previously identified by the P.I. To accomplish the first half of this aim, in depth studies of neutrophil bactericidal activity (measured as bactericidal capacity and rate) will be performed on cells from thermally injured patients and correlated with studies of neutrophil metabolism (cyclic nucleotides, energy charge, NAD levels, oxygen consumption, energy stores). The second half of this aim will be devoted to determining why endogenous lymphocyte blastogenesis, measured as the SBT, is increased, especially during sepsis, even when mitogen stimulated blastogenesis is impaired. The phenomenon of increased endogenous and decreased stimulated activity could theoretically be explained by increased suppressor cell activity, helper cell """"""""exhaustion"""""""", or changes in the metabolic state of the cells. Therefore, lymphocyte subpopulation analysis will be performed (monoclonal antibodies and flow cytometry) and correlated with the results of selective lymphocyte subpopulation depletion studies (complement lysis), and studies of the levels and ratios of cAMP and cGMP. By clarifying the mechanisms of immune dysfunction that occurs after thermal injury, this project may ultimately lead to new therapeutic strategies, which will improve patient survival.
| Deitch, E A; Bridges, R M; Dobke, M et al. (1987) Burn wound sepsis may be promoted by a failure of local antibacterial host defenses. Ann Surg 206:340-8 |
| Kupper, T S; Deitch, E A; Baker, C C et al. (1986) The human burn wound as a primary source of interleukin-1 activity. Surgery 100:409-15 |
