Research Center, Maisonneuve-Rosemont Hospital, and Department of Pathology and Cell Biology, University of Montréal, Montréal, QC, Canada H1T 2M4.
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14983-8. doi: 10.1073/pnas.1206641109. Epub 2012 Aug 27.
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 ω-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. In mice, 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.
中性粒细胞的异常激活导致急性肺损伤（ALI）的发病机制。细胞凋亡对于清除炎症组织中的中性粒细胞和及时缓解炎症至关重要。内源性脂质介质 RvE1 是一种从 ω-3 多不饱和脂肪酸二十碳五烯酸衍生而来的物质，具有促解决作用。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 RvE1 对中性粒细胞凋亡和中性粒细胞介导的肺部炎症的影响。RvE1 与人中性粒细胞孵育可加速调理后的大肠杆菌或酵母吞噬作用引起的细胞凋亡。RvE1 通过白细胞三烯 B4 受体 BLT1 增强 NADPH 氧化酶衍生的活性氧生成，随后激活半胱氨酸蛋白酶-8 和半胱氨酸蛋白酶-3。RvE1 还减弱了髓过氧化物酶、血清淀粉样蛋白 A 和细菌 DNA 介导的 ERK 和 Akt 凋亡抑制信号，通过诱导线粒体功能障碍，将促生存和抗生存信号的平衡向凋亡倾斜。在小鼠中，RvE1 治疗通过促进中性粒细胞凋亡及其被巨噬细胞清除，增强了气管内滴注或腹腔内注射活大肠杆菌或气管内滴注角叉菜胶加髓过氧化物酶引起的已建立的中性粒细胞介导的肺损伤的解决。pan-caspase 抑制剂 zVAD-fmk 可预防 RvE1 的作用。这些结果确定了一种机制，即通过促进吞噬作用诱导的中性粒细胞凋亡和减轻有效的抗凋亡信号，RvE1 可以增强急性肺炎症的解决。
