BIOCHEMISTRY OF NEUTROPHIL DYSFUNCTION IN THERMAL INJURY

热损伤诱导的主要效应器功能的深刻抑郁症， 中性粒细胞的机制知之甚少。 最近的研究来自 我们的实验室利用热损伤的豚鼠模型， 细胞内环磷酸腺苷（cAMP） 在热损伤时升高，这反过来又降低了 这些细胞的杀菌活性。 超氧阴离子（O2-）产生 在用甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMet-Leu-）刺激后， Phe）在该模型中同时减少，这表明 改变也可能与细胞内cAMP的升高有关。 的 在本申请中提出的研究将识别生物化学事件 导致氧气的产生，而氧气的产生会因豚鼠的热损伤而改变 猪模型（即，肌醇磷酸生产，1，2-二酰基甘油 产生、升高胞浆钙和蛋白激酶C 激活）。 此外，细胞内cAMP的参与， 介导这些改变和对fMet的适应性趋化反应， 我们在这个模型中观察到的Leu-Phe将被确定。 修饰fMet-Leu-Phe受体的亲和力作为一种可能的方法。 对fMet-Leu-Phe的适应性趋化反应的机制也将 被探索。 腺苷酸环化酶系统参与了 热损伤后中性粒细胞内cAMP升高， 循环因子在介导这种和其他生化反应中的作用 与中性粒细胞功能障碍相关的改变将在 豚鼠模型 此外，目前的概念来自我们的 动物研究将进行确证性临床研究， 人类 了解中性粒细胞功能障碍的生化基础 热损伤后是确定是否 这种改变可以通过药物干预来逆转， 受伤的病人和这种干预的目标部位。 基本 从这项研究中产生的概念也可能适用于中性粒细胞 与其他形式的创伤相关的功能障碍。

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.