Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction
Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction
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吡格列酮通过改善肠屏障功能减轻实验性结肠炎相关的痛觉过敏
DOI：
10.1007/s10753-019-01138-3
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发表时间：
2020-01-27
期刊：
影响因子：
5.1
通讯作者：
Ma, Zhengliang
中科院分区：
文献类型：
--
作者：
Huang, Yulin;Wang, Chenchen;Ma, Zhengliang
结肠炎期间肠黏膜完整性受损涉及到过氧化物酶体增殖物激活受体γ (PPAR γ)， PPAR γ是肠黏膜稳态中重要的抗炎因子，是结肠炎的潜在靶点。复发性慢性疼痛是结肠炎的重要病理特征。然而，PPAR γ在结肠炎相关痛觉过敏中的潜在功能尚不清楚。本研究旨在探讨吡格列酮在葡聚糖硫酸钠（DSS）诱导的肠道炎症过程中，通过PPAR γ紧密连接蛋白依赖机制缓解结肠炎相关疼痛超敏反应的生物学作用。建立dss诱导的C57BL/6小鼠结肠炎模型。通过免疫荧光、苏木精和伊红（H&E）染色、western blot分析和足部停药机械阈值测定，观察吡格列酮（25 mg/kg， IP注射液）给药6 d后结肠炎引起的肠黏膜屏障损伤和痛感过敏的变化。DSS治疗后，足爪退断机械阈值显著降低。随访数据显示，系统给予PPAR γ激动剂吡格列酮可通过修复肠黏膜屏障改善dss诱导的结肠炎和结肠炎相关痛觉过敏的发生。PPAR γ信号上调紧密连接蛋白ZO-1和Claudin-5，进而促进肠道屏障功能的改善。此外，吡格列酮抑制结肠中ERK和NF-kappa B的磷酸化，降低结肠脊柱组织中炎症细胞因子的水平。此外，全身吡格列酮治疗抑制小胶质细胞和星形胶质细胞的激活，以及dss诱导的脊髓NR2B亚基磷酸化，这与疼痛行为相一致。吡格列酮通过直接上调紧密连接蛋白改善肠粘膜屏障的完整性，改善dss诱导的结肠炎和减轻结肠炎相关的机械痛觉过敏。PPAR -紧密连接蛋白信号可能是治疗结肠炎相关慢性疼痛的潜在治疗靶点。
Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-gamma (PPAR gamma), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPAR gamma in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain hypersensitivity by a PPAR gamma tight junction protein-dependent mechanism during the course of dextran sodium sulfate (DSS)-induced intestinal inflammation. The DSS-induced colitis model was generated in C57BL/6 mice. Changes in colitis induced the injury of intestinal mucosal barrier and hyperalgesia after a 6-day treatment of pioglitazone (25 mg/kg, IP injection) were assessed through immunofluorescent, hematoxylin and eosin (H&E) staining, western blot analysis, and determination of paw withdrawal mechanical threshold. A significant reduction of paw withdrawal mechanical threshold occurred after DSS treatment. Follow-up data showed that systematic administration of PPAR gamma agonist pioglitazone ameliorated the DSS-induced colitis and the development of colitis-associated hyperalgesia by repairing the intestinal mucosal barrier. The tight junction proteins ZO-1 and Claudin-5 were upregulated by PPAR gamma signaling, which in turn promoted the improvement of intestinal barrier function. Moreover, pioglitazone inhibited phosphorylation of ERK and NF-kappa B in the colon and decreased the levels of inflammatory cytokines in both colon spine tissues. Furthermore, systemically pioglitazone treatment inhibited the activation of microglia and astrocytes, as well as DSS-induced phosphorylation of NR2B subunit in spinal cord, which was correspondingly consistent with the pain behavior. Pioglitazone ameliorates DSS-induced colitis and attenuates colitis-associated mechanical hyperalgesia, with improving integrity of the intestinal mucosal barrier by directly upregulating tight junction proteins. The PPAR gamma-tight junction protein signaling might be a potential therapeutic target for the treatment of colitis-associated chronic pain.