Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Neurogastroenterol Motil. 2019 Feb;31(2):e13477. doi: 10.1111/nmo.13477. Epub 2018 Oct 4.
Chronic psychological stress is associated with increased intestinal epithelial permeability and visceral hyperalgesia. Lubiprostone, an agonist for chloride channel-2, promotes secretion and accelerates restoration of injury-induced epithelial barrier dysfunction. The mechanisms underlying how lubiprostone regulates colon epithelial barrier function and visceral hyperalgesia in chronic stress remain unknown.
Male rats were subjected to water avoidance stress for 10 consecutive days. Lubiprostone was administered daily during the stress phase. Visceromotor response to colorectal distension was measured. Human colon crypts and cell lines were treated with cortisol and lubiprostone. The transepithelial electrical resistance and FITC-dextran permeability were assayed. Chromatin immunoprecipitation was conducted to assess glucocorticoid receptor binding at tight junction gene promoters.
Lubiprostone significantly decreased chronic stress-induced visceral hyperalgesia in the rat (P < 0.05; n = 6). WA stress decreased occludin and claudin-1 and increased claudin-2 in rat colon crypts, which was prevented by lubiprostone. Cortisol treatment induced similar alterations of tight junction protein expression in Caco-2/BBE cells (P < 0.05) and significantly changed paracellular permeability in monolayers (P < 0.01). These changes were blocked by lubiprostone. Glucocorticoid receptor and its binding at occludin promoter region were decreased in cortisol-treated cells and human colon crypts, which was largely reversed by lubiprostone. In rat colonic cells, glucocorticoid receptor and its co-chaperone proteins were down-regulated after corticosterone treatment and lubiprostone reversed these changes.
CONCLUSIONS & INFERENCES: Lubiprostone preferentially prevents chronic stress-induced alterations of intestinal epithelial tight junctions, barrier function, and visceral hyperalgesia that was associated with modulation of glucocorticoid receptor expression and function.
慢性心理应激与肠上皮通透性增加和内脏痛觉过敏有关。鲁比前列酮是氯离子通道 2 的激动剂，可促进分泌并加速损伤诱导的上皮屏障功能障碍的恢复。鲁比前列酮调节慢性应激下结肠上皮屏障功能和内脏痛觉过敏的机制尚不清楚。
雄性大鼠连续 10 天进行避水应激。在应激期每天给予鲁比前列酮。测量结直肠扩张时的内脏运动反应。用皮质醇和鲁比前列酮处理人结肠隐窝和细胞系。测定跨上皮电阻和 FITC-葡聚糖通透性。进行染色质免疫沉淀以评估紧密连接基因启动子处的糖皮质激素受体结合。
鲁比前列酮显著降低了大鼠慢性应激引起的内脏痛觉过敏（P<0.05；n=6）。WA 应激降低了大鼠结肠隐窝中的紧密连接蛋白 occludin 和 claudin-1，并增加了 claudin-2，鲁比前列酮可预防这种变化。皮质醇处理诱导 Caco-2/BBE 细胞中紧密连接蛋白表达的类似改变（P<0.05），并显著改变单层细胞的旁通透性（P<0.01）。鲁比前列酮阻断了这些变化。皮质醇处理的细胞和人结肠隐窝中糖皮质激素受体及其在闭合蛋白启动子区域的结合减少，鲁比前列酮在很大程度上逆转了这种减少。在大鼠结肠细胞中，皮质酮处理后糖皮质激素受体及其共伴侣蛋白表达下调，鲁比前列酮逆转了这些变化。
鲁比前列酮优先预防慢性应激引起的肠上皮紧密连接、屏障功能和内脏痛觉过敏的改变，这与糖皮质激素受体表达和功能的调节有关。
