BIOCHEMISTRY OF NEUTROPHIL DYSFUNCTION IN THERMAL INJURY

点击翻译按钮获取中文摘要

Thermal injury induces a profound depression in major effector functions of neutrophils by mechanisms that are poorly understood. Recent studies from our laboratory utilizing a guinea pig model of thermal injury have demonstrated that intracellular cyclic-3',5'-adenosine monophosphate (cAMP) is elevated in response to thermal injury, and this in turn depresses the bactericidal activity of these cells. Superoxide anion (O2-) production following stimulation with formylmethionyl-leucyl-phenylalanine (fMet-Leu- Phe) is reduced concomitantly in this model, suggesting that this alteration also may be related to elevation of intracellular cAMP. The studies proposed in this application will identify the biochemical events leading to O2- production that are altered by thermal injury in the guinea pig model (i.e., inositol phosphate production, 1,2-diacylglycerol production, elevation of cytosolic calcium and protein kinase C activation). In addition, the involvement of intracellular cAMP in mediating these alterations and the adaptive chemotactic response to fMet- Leu-Phe that we have observed in this model will be determined. Modification of the affinity of fMet-Leu-Phe receptors as a possible mechanism for the adaptive chemotactic response to fMet-Leu-Phe also will be explored. The involvement of the adenylate cyclase system in the elevation of intracellular cAMP in neutrophils following thermal injury and the role of circulating factors in mediating this and other biochemical alterations associated with neutrophil dysfunction will be determined in the guinea pig model. In addition, current concepts derived from our animal studies will be subjected to confirmatory clinical investigation in humans. Understanding the biochemical basis for neutrophil dysfunction following thermal injury is an essential first step in determining whether this alteration can be reversed by pharmacologic intervention in thermally injured patients and the target sites for such intervention. Basic concepts resulting from this research also may be applicable to neutrophil dysfunction associated with other forms of trauma.