A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation
A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation
复制标题
DOI：
10.1182/blood-2013-04-496661
复制
发表时间：
2013-07-25
期刊：
影响因子：
20.3
通讯作者：
Perretti, Mauro
中科院分区：
文献类型：
--
作者：
Brancaleone, Vincenzo;Gobbetti, Thomas;Perretti, Mauro
内源性保护途径可减轻无菌或感染性损伤后炎症的过度反应。在这里，我们报告甲酰基肽受体2（Fpr2/3）缺失小鼠表现出一种主要表型，观察到肠系膜动脉缺血再灌注（IR）损伤，血管炎症加剧，其特征是通过活体显微镜观察到明显的中性粒细胞粘附和外渗。对 Fpr2/3 内源性激动剂的分析表明，缺血期间血小板/中性粒细胞聚集体会产生脂氧素 A(4) (LXA(4))：这种细胞反应在 Fpr2/3(-/-) 小鼠中减弱；因此，LXA(4)水平在缺血30分钟后较低，并且与再灌注（45-180分钟）阶段血管炎症增强相关。外源性递送 LXA(4) 可减轻 Fpr2/3(+/+) 小鼠中 IR 介导的炎症，但不能减轻 Fpr2/3(+/+) 小鼠；相反，Fpr2/3拮抗剂使Fpr2/3(+/+)小鼠的血管表型偏向于Fpr2/3(-/-)动物。这种基于 LXA(4) 的电路可以被阿司匹林 (30-100 mg/kg) 激活，从而在野生型小鼠中触发 15-epi-LXA(4) 的形成，但对 Fpr2/3(-/-) 小鼠也有效。总之，我们提出，在缺血期间，中性粒细胞 Fpr2/3 通过循环 LXA(4) 的快速生成控制血小板/中性粒细胞聚集，进而调节再灌注阶段明显的下游血管炎症反应。
Endogenous protective pathways mitigate the overshooting of inflammation after sterile or infectious injury. Here we report that formyl peptide receptor 2 (Fpr2/3) null mice display a major phenotype with exacerbated vascular inflammation observed postischemia reperfusion (IR) injury of the mesenteric artery, characterized by marked neutrophil adhesion and extravasation as visualized by intravital microscopy. Analysis of endogenous agonists for Fpr2/3 revealed that lipoxin A(4) (LXA(4)) was generated by platelet/neutrophil aggregates during ischemia: this cellular response was attenuated in Fpr2/3(-/-) mice; hence, LXA(4) levels were lower after 30 minutes' ischemia, and associated with augmented vascular inflammation in the reperfusion (45-180 minutes) phase. Exogenous delivery of LXA(4) attenuated IR-mediated inflammation in Fpr2/3(+/+) but not Fpr2/3(+/+) mice; conversely, an Fpr2/3 antagonist skewed the vascular phenotype of Fpr2/3(+/+) mice to that of Fpr2/3(-/-) animals. Such LXA(4)-based circuit could be activated by aspirin (30-100 mg/kg), which triggered formation of 15-epi-LXA(4) in wild-typemice, yet it was effective in Fpr2/3(-/-) mice. In summary, we propose that during ischemia, neutrophil Fpr2/3 controls platelet/neutrophil aggregates with the rapid generation of circulating LXA(4), which in turn modulates downstream vascular inflammatory responses evident during the reperfusion phase.