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

Abstract

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

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

“…I/R was performed with 30-min ischemia and 90-min reperfusion; intravital microscopy of the mesentery was conducted as described previously (18). One to three postcapillary venules were analyzed for the extent of cell rolling, adhesion, and emigration.…”

“…I/R of the mesenteric microcirculation followed by intravital microscopy allowed monitoring of the processes of leukocyte rolling, adhesion, and emigration (18). The dose of 0.1 μg was selected and administered before reperfusion.…”

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

“…The homeostatic functions of proresolving and tissue-protective pathways are now emerging in several immune contexts, including arthritis, colitis, periodontal pathologies (5), and ischemia/reperfusion damage (13). The complex biological functions affected by Fpr2/3 afforded efficacy against polymicrobial sepsis downstream of positive modulation of multiple life-saving processes through a single receptor determinant.…”

“…LXA 4 and AnxA1 are largely inactive in a transgenic mouse that lacks both murine genes (12) as shown in models of acute inflammation and ischemia-reperfusion injury (12)(13)(14)(15). Herein we establish the patho-pharmacology of Fpr2/3 in experimental polymicrobial sepsis as a way to validate the human Significance Sepsis defines a syndrome with poor clinical management characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state.…”

Modulation of Voltage-Dependent and Inward Rectifier Potassium Channels by 15-Epi-Lipoxin-A4 in Activated Murine Macrophages: Implications in Innate Immunity

“…The endogenous protective role of ALX mediating the biological actions of lipoxins has been demonstrated in mice overexpressing the human ALX in myeloid cells (25). A recent study in which vascular inflammation in wild-type and ALX 2/2 mice was compared demonstrates that ALX activation controls platelet/neutrophil aggregates to afford LXA 4 synthesis, inhibiting vascular inflammation on reperfusion, at the time that aspirin can jumpstart this circuit by triggering e-LXA 4 synthesis (26). In the present work, we have studied the effects of e-LXA 4 on K v and K ir in bone marrow-derived macrophages (BMDM) under different activation conditions.…”