A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation

摘要

Endogenous protective pathways mitigate the overshooting of inflammation after sterile\udor infectious injury. Here we report that formyl peptide receptor 2 (Fpr2/3) null mice display\uda major phenotype with exacerbated vascular inflammation observed postischemia reperfusion\ud(IR) injury of the mesenteric artery, characterized by marked neutrophil adhesion\udand extravasation as visualized by intravitalmicroscopy. Analysis of endogenous agonists\udfor Fpr2/3 revealed that lipoxin A4 (LXA4) was generated by platelet/neutrophil aggregates\udduring ischemia: this cellular response was attenuated in Fpr2/32/2 mice; hence, LXA4\udlevels were lower after 30 minutes’ ischemia, and associated with augmented vascular\udinflammation in the reperfusion (45-180 minutes) phase. Exogenous delivery of LXA4\udattenuated IR-mediated inflammation in Fpr2/31/1 but not Fpr2/32/2 mice; conversely, an\udFpr2/3 antagonist skewed the vascular phenotype of Fpr2/31/1 mice to that of Fpr2/32/2\udanimals. Such LXA4-based circuit could be activated by aspirin (30-100 mg/kg), which\udtriggered formation of 15-epi-LXA4 in wild-typemice, yet it was effective in Fpr2/32/2 mice. In summary,we propose that during ischemia,\udneutrophil Fpr2/3 controls platelet/neutrophil aggregates with the rapid generation of circulating LXA4, which in turn modulates\uddownstream vascular inflammatory responses evident during the reperfusion phase.