期刊
FASEB JOURNAL
卷 29, 期 5, 页码 2161-2171出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-263160
关键词
ischemia /reperfusion; inflammation; FPR2/ALX; Annexin A1
资金
- Higher Education Funding Council for England
- MRC [MC_PC_12015] Funding Source: UKRI
Ischemia/reperfusion (I/R) injury following stroke can worsen patient outcome through excess inflammation. This study investigated the pharmacologic potential of targeting an endogenous anti-inflammatory circuit via formyl peptide receptor (FPR) 2/lipoxin receptor (ALX) (Fpr2/3 in mouse) in global cerebral I/R. Mice (C57BL/6 and Fpr2/3(-/-)) were subjected to bilateral common carotid artery occlusion, followed by reperfusion and treatment with FPR agonists: AnxA1(Ac2-26) [Annexin A1 mimetic peptide (Ac-AMVSEFLKQAWFIENEEQEYVQTVK), 2.5 mu/kg] and 15-epimer-lipoxin A4 (15-epi-LXA(4); FPR2/ALX specific, 12.5 and 100 ng/kg). Leukocyte-endothelial (L-E) interactions in the cerebral microvasculature were then quantified in vivo using intravital fluorescence microscopy. 15-epi-LXA(4) administration at the start of reperfusion reduced L-E interactions after 40 min (which was sustained at 2 h with high-dose 15-epi-LXA(4)) to levels seen in sham-operated animals. AnxA1(Ac2-26) treatment decreased leukocyte adhesion at 40 min and all L-E interactions at 2 h (up to 95%). Combined treatment with AnxA1(Ac2-26) plus FPR antagonists t-Boc-FLFLF (250 ng/kg) or WRW4 (FPR2/ALX selective, 1.4 mu/kg) abrogated the effects of AnxA1(Ac2-26) fully at 40 min. Antagonists were less effective at 2 h, which we demonstrate is likely because of their impact on early L-E interactions. Our findings indicate that FPR2/ALX activity elicits considerable control over vascular inflammatory responses during cerebral I/R and, therefore, provide evidence that targeting FPR2/ALX may be beneficial for patients who suffered from stroke.
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