Resolution of Inflammation by Resolvin D1 Is Essential for Peroxisome Proliferator-activated Receptor-γ-mediated Analgesia during Postincisional Pain Development in Type 2 Diabetes
Resolution of Inflammation by Resolvin D1 Is Essential for Peroxisome Proliferator-activated Receptor-γ-mediated Analgesia during Postincisional Pain Development in Type 2 Diabetes
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DOI：
10.1097/aln.0000000000000892
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发表时间：
2015-12-01
期刊：
影响因子：
8.8
通讯作者：
Kanmura, Yuichi
中科院分区：
文献类型：
--
作者：
Saito, Takayuki;Hasegawa-Moriyama, Maiko;Kanmura, Yuichi
背景：糖尿病患者术后急性炎症后伤口愈合过程受损。改变的巨噬细胞功能与糖尿病中延迟的组织修复和疼痛发展有关。虽然过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）激动剂被用于治疗糖尿病，但其术后镇痛效果尚未被评估。方法：将PPAR激动剂罗格列酮（rosiglitazone，rosi）注射于糖尿病（db/db）小鼠切口部位，并加入消退素（resolvin，Rv）D1，一种参与炎症消退的脂质介质。结果：罗格列酮和RvD1可减轻db/db（db）小鼠的机械性痛觉过敏，而单独罗格列酮在第4天不改变机械阈值（db rosi + RvD1 vs. db rosi：0.506 ± 0.106 vs. 0.068 ± 0.12）和7（0.529 ± 0.184 vs. 0.153 ± 0.183）（每组n = 10）。在对照m/m小鼠中，罗格列酮诱导的镇痛作用被花生四烯酸5-脂氧合酶小干扰RNA敲低逆转，但这些都恢复了RvD1。在罗格列酮和RvD1处理的db/db小鼠中，中性粒细胞的局部浸润显著减少，总TdT介导的dUTP缺口末端标记细胞减少。罗格列酮诱导的表型转化的浸润巨噬细胞从M1到M2的加速受损db/db小鼠，但它是有效地恢复RvD1在db/db wounds.Conclusions：在糖尿病，外源性管理RvD1是必不可少的PPAR介导的镇痛在发展中的切口后疼痛。RvD1加速的炎症消退可能促进PPAR介导的巨噬细胞向M2表型极化。
Background: The wound healing process following acute inflammation after surgery is impaired in diabetes. Altered macrophage functions are linked to delayed tissue repair and pain development in diabetes. Although peroxisome proliferator-activated receptor (PPAR)- agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated.Methods: The PPAR agonist rosiglitazone (rosi) was injected at the incision site of diabetic (db/db) mice with resolvin (Rv) D1, a lipid mediator involved in resolution of inflammation. Pain-related behavior, neutrophil infiltration, phagocytosis, and macrophage polarity were assessed for 7 days postoperatively.Results: Rosiglitazone and RvD1 alleviated mechanical hyperalgesia in db/db (db) mice, whereas rosiglitazone alone did not alter mechanical thresholds on days 4 (db rosi + RvD1 vs. db rosi: 0.506 0.106 vs. 0.068 +/- 0.12) and 7 (0.529 +/- 0.184 vs. 0.153 +/- 0.183) after incision (n = 10 per group). In control m/m mice, the rosiglitazone-induced analgesic effects were reversed by knockdown with arachidonate 5-lipoxygenase small interfering RNA, but these were restored by addition of RvD1. In db/db mice treated with rosiglitazone and RvD1, local infiltration of neutrophils was markedly reduced, with an associated decrease in total TdT-mediated dUTP nick-end labeling cells. Acceleration of rosiglitazone-induced phenotype conversion of infiltrated macrophages from M1 to M2 was impaired in db/db mice, but it was effectively restored by RvD1 in db/db wounds.Conclusions: In diabetes, exogenous administration of RvD1 is essential for PPAR-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPAR-mediated macrophage polarization to the M2 phenotype.