Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation
Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation
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DOI：
10.1073/pnas.1206641109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Filep, Janos G.
中科院分区：
文献类型：
--
作者：
El Kebir, Driss;Gjorstrup, Per;Filep, Janos G.
不适当的中性粒细胞活化有助于急性肺损伤（ALI）的发病机制。细胞凋亡对于从炎症组织中清除中性粒细胞和及时解决炎症至关重要。Resolvin E1（RvE 1）是一种内源性脂质介质，来源于omega-3多不饱和脂肪酸二十碳五烯酸，具有促分解作用。由于促生存和促凋亡信号的平衡决定了中性粒细胞的命运，我们研究了RvE 1对小鼠中性粒细胞凋亡和嗜中性粒细胞介导的肺部炎症的结果的影响。培养人中性粒细胞与RvE 1加速细胞凋亡诱发的吞噬调理大肠杆菌或酵母菌。RvE 1通过白三烯B-4受体BLT 1增强NADPH氧化酶衍生的活性氧物质的产生和随后的caspase-8和caspase-3的活化。RvE 1还减弱了ERK和Akt介导的髓过氧化物酶、血清淀粉样蛋白A和细菌DNA的凋亡抑制信号，通过诱导线粒体功能障碍将促生存信号和抗生存信号的平衡向凋亡转移。在小鼠中，RvE 1处理增强了由气管内滴注或腹腔注射活大肠杆菌引起的嗜中性粒细胞介导的肺损伤的消退。大肠杆菌或腹膜内滴注卡拉胶加髓过氧化物酶通过促进中性粒细胞凋亡和它们被巨噬细胞清除。RvE 1的作用被泛半胱天冬酶抑制剂zVAD-favor阻断。这些结果确定了一种机制，即促进吞噬诱导的中性粒细胞凋亡和减轻有效的抗凋亡信号，通过该机制RvE 1可以增强急性肺部炎症的消退。
Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B-4 receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis-suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro-and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. Inmice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.