ANTIINFLAMMATORY PHENOTYPE OF NEUTROPHILS

新的研究结果表明，持续的中性粒细胞活化诱导环氧合酶II。 这种新认识的途径表明自分泌途径，下调中性粒细胞的行动，使阿司匹林触发异脂氧素的产生。我们最近已经证明，异脂氧素是体内促炎信号的有效抑制剂，并通过LXA 4受体在基因水平上发挥其作用。 我们将检验以下假设：PMN的持续激活诱导向抗炎表型的转变，这反映在类花生酸谱和受体表达中，并且异脂氧素在基因水平诱导这种表型。本提案将侧重于：i）在表达考克斯II的中性粒细胞中建立类二十烷酸谱，并确定这些细胞在阿司匹林存在下是否产生异脂氧素ii）确定考克斯II诱导和细胞因子暴露是否诱导中性粒细胞中炎症受体的差异表达iii）阐明LXA 4受体在调节细胞因子、受体和生物合成途径的表达中的作用，以及确定LXA 4受体途径在明显的中性粒细胞活化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，并可能提供控制中性粒细胞介导的组织损伤的新药理学工具。

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.