Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation
Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation
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DOI：
10.1007/s00535-006-1942-7
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发表时间：
2007-01-01
影响因子：
6.3
通讯作者：
Fukudo, Shin
中科院分区：
文献类型：
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作者：
Fukudo, Shin
促肾上腺皮质激素释放激素（CRH）是脑-肠轴应激反应的主要介质。肠易激综合征（IBS）被认为是一种与对压力的过度反应有关的脑-肠联系障碍。我们首先发现，外周注射CRH加重了IBS患者的内脏感觉运动功能以及促肾上腺皮质激素（ACTH）反应。然后，我们给IBS患者使用α-螺旋CRH（α-hCRH），一种非选择性CRH受体拮抗剂。直肠电刺激诱导IBS患者结肠的运动指数显著高于对照组。这种反应在IBS患者中被显著抑制，但在施用ahCRH后的对照中未被抑制。给药ahCRH诱导对照组的恒压袋体积显著增加，但IBS患者的恒压袋体积未显著增加。ahCRH显著降低IBS患者电刺激诱发的腹痛和焦虑的纵坐标。血浆ACTH和血清皮质醇通常不受ahCRH抑制。最后，给予CRH 1受体（CRH-R1）特异性拮抗剂可阻断结直肠扩张诱导的大鼠内脏感知敏感化。此外，CRH-R1拮抗剂预处理阻断结直肠扩张诱导的焦虑，这是用高架十字迷宫，在大鼠。支持外周CRH和CRH-R1在脑-肠致敏中发挥重要作用的证据越来越多。几项研究已经确定了免疫反应性CRH和尿皮质素以及CRH-R1和CRH-R2 mRNA在人类结肠粘膜。此外，逆转录-聚合酶链反应揭示了CRH-R1 mRNA在豚鼠的肌间神经丛和粘膜下神经丛中的表达。CRH的应用已被证明引起与肌间和粘膜下神经元兴奋性升高相关的去极化反应。另一方面，已报道外周注射CRH对结肠分泌和运动功能以及通透性产生离散效应。CRH-R1和CRH-R2之间存在功能差异。例如，CRH-R1的激活引起促炎反应，而CRH-R2的刺激引起抗炎变化。此外，有证据表明CRH-R1和CRH-R2在内脏伤害感受中的作用截然不同。CRH-R1参与内脏痛的促伤害性作用，CRH-R2介导抗伤害性反应。这些发现表明CRH在IBS的应激相关病理生理学中的主要作用，并可能在肠粘膜炎症中发挥作用。
Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with exaggerated response to stress. We first showed that peripheral administration of CRH aggravated visceral sensorimotor function as well as adrenocorticotropic hormone (ACTH) response in IBS patients. We then administered a-helical CRH (alpha hCRH), a non-selective CRH receptor antagonist among IBS patients. Electrical stimulation of the rectum induced significantly higher motility indices of the colon in IBS patients than in the controls. This response was significantly suppressed in IBS patients but not in the controls after administration of ahCRH. Administration of ahCRH induced a significant increase in the barostat bag volume of the controls but not in that of IBS patients. ahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by electrical stimulation in IBS patients. Plasma ACTH and serum cortisol were generally not suppressed by ahCRH. Last, administration of CRH1-receptor (CRH-R1) specific antagonist blocked colorectal distention-induced sensitization of the visceral perception in rats. Moreover, pretreatment with CRH-R1 antagonist blocked colorectal distention-induced anxiety, which was measured with elevated plus-maze, in rats. Evidence supporting the concept that peripheral CRH and CRH-R1 play important roles in brain-gut sensitization is increasing. Several studies have identified immunoreactive CRH and urocortin as well as CRH-R1 and CRH-R2 mRNAs in human colonic mucosa. In addition, reverse transcription-polymerase chain reaction has revealed the expression of CRH-R1 mRNA in both the myenteric and submucosal plexus in the guinea pig. Application of CRH has been shown to evoke depolarizing responses associated with elevated excitability in both myenteric and submucosal neurons. On the other hand, peripheral injection of CRH has been reported to induce discrete effects on colonic secretory and motor function, and permeability. There are functional differences between CRH-R1 and CRH-R2. For instance, activation of CRH-R1 causes a proinflammatory response, whereas stimulation of CRH-R2 provokes anti-inflammatory changes. In addition, there is evidence of the contrasting roles of CRH-R1 and CRH-R2 in visceral nociception. While CRH-R1 is involved in the pro-nociceptive effects of visceral pain, CRH-R2 mediates an anti-nociceptive response. These findings suggest the major role of CRH in stress-related pathophysiology of IBS and possibly in inflammation of the intestinal mucosa.