Severe trauma of burn injury causes changes in the function of circulating white cells (neutrophils) including impaired ability to migrate to a site of infection and to kill subsequently encountered micro-organisms. The significance of these changes is that such patients are at increased risk of infection, and most deaths in this generally young patient population are due to uncontrolled infection. The mechanism(s) producing the described neutrophil abnormalities have not been elucidated. We have been studying the hypothesis that the observed cellular abnormalities are due to exposure to the complement-derived product C5a, known to be a major in vivo chemoattractant and effector of neutrophil function and formed following tissue injury of infection. C5a-mediated effects on neutrophils include: partial degranulation with increased numbers of C3b (opsonic) and FMLP (chemotactic) receptors; increased migratory movement; and increased aggregation and adherence. Our previous work has supported the hypothesis that extensive degranulation and deactivation of neutrophils by C5a, and easily demonstrable in vitro phenomenon, occurs in traumatized patients and may account for the dysfunctional state noted. However, exposure of normal neutrophils to the concentrations of C5a we have measured in such patients causes enhancement of certain neutrophil functions. This finding suggests the hypothesis that the fall-off in migratory and other neutrophil responses to the low levels observed is due to an initial C5a-mediated hyperresponsiveness of patient cells and subsequent degranulation with secretion of toxic bactericidal enzymes and inflammatory mediators at a site of injury. A subsidiary hypothesis of this project is that hyperresponsiveness is mediated through the expression of cryptic receptors. The experimental design includes an examination of the in vitro effects of purified C5a on normal neutrophil function and receptor populations. Following characterization of the effects of C5a on neutrophil receptors, time-course studies of receptor populations and receptor-mediated functions will be performed on neutrophils from patients with extensive tissue injury (burns and trauma). This study will expand our understanding of neutrophil control mechanisms and define avenues for pharmacologic modulation of neutrophil function following burn injury.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R23)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Cincinnati
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Solomkin, J S (1990) Neutrophil disorders in burn injury: complement, cytokines, and organ injury. J Trauma 30:S80-5
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