ANTIINFLAMMATORY PHENOTYPE OF NEUTROPHILS

新的发现表明，持续的中性粒细胞激活诱导环氧合酶II。这一新发现的途径表明，一种自分泌途径下调中性粒细胞的活动，并使阿司匹林触发的异脂蛋白的产生。我们最近证明，异脂蛋白是体内促炎信号的有效抑制剂，并通过LXA4受体在基因水平发挥部分作用。我们将检验这样的假设，即PMN的持续激活诱导了向抗炎表型的转换，这反映在二十烷基类化合物和受体的表达中，并且异脂蛋白在基因水平上诱导了这种表型。目前的建议将集中在：i)建立在PMN中表达COX II的二十聚糖类化合物，并确定这些细胞在阿司匹林II存在的情况下是否产生异脂蛋白)确定COX II诱导和细胞因子暴露是否诱导中性粒细胞炎症受体的差异表达III)阐明LXA4受体在调节细胞因子、受体和生物合成途径表达中的作用，以及确定LXA4受体途径在明显的中性粒细胞激活的体内表型中是否完整。这些特定目标的结果将阐明促进炎症自我消退的内源性生化途径，并可能为控制中性粒细胞介导的组织损伤提供新的药理学工具。

New findings demonstrate that sustained neutrophil activation induces cyclooxygenase II. This newly recognized pathway suggests an autocrine pathway that down-regulates neutrophil action and enables generation of aspirin-triggered iso-lipoxins. We have recently demonstrated that iso-lipoxins are potent inhibitors of pro-inflammatory signals in vivo and exert some of their action at the gene level via a LXA4-receptor. We shall test the hypothesis that sustained activation of PMN induces a switch towards an anti-inflammatory phenotype that is reflected in eicosanoid profiles and receptor expression, and that iso- lipoxins induce this phenotype at the gene level. The present proposal will focus on: i) Establishing the eicosanoid profile in PMN that express COX II and determine if these cells generate iso-lipoxins in the presence of aspirin ii) determine if COX II induction and cytokine exposure induces differential expression of inflammatory receptors in neutrophils iii) elucidate the role for LXA4-receptor in modulating expression of cytokines, receptors and biosynthetic pathways, as well as determine if LXA4-receptor pathways are intact in an in vivo phenotype of overt neutrophil activation. Results from these specific aims will elucidate endogenous biochemical pathways that promote the self resolution of inflammation and may provide novel pharmacological tools in controlling neutrophil mediated tissue injury.