Altered colonic sensory and barrier functions by CRF: roles of TLR4 and IL-1
Altered colonic sensory and barrier functions by CRF: roles of TLR4 and IL-1
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DOI：
10.1530/joe-18-0441
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发表时间：
2018-11-01
影响因子：
4
通讯作者：
Okumura, Toshikatsu
中科院分区：
文献类型：
--
作者：
Nozu, Tsukasa;Miyagishi, Saori;Okumura, Toshikatsu
内脏异常性疼痛和结肠通透性增加被认为是肠易激综合征（IBS）的重要病理生理学。促肾上腺皮质激素释放因子（CRF）和免疫介导的机制已被提出，以促进这些变化在IBS，但确切的作用尚未确定。我们在大鼠体内探索了这些问题。内脏反应的阈值，即，电生理学测量由结肠气囊扩张引起的腹部肌肉收缩。通过定量结肠组织中吸收的伊文思蓝来估计结肠渗透性。腹腔注射CRF可使细胞通透性增加，但可被非选择性CRF受体拮抗剂astressin所阻断，而选择性CRF受体亚型2（CRF 2）拮抗剂astressin（2）-B则无此作用，选择性CRF 2激动剂Urocortin 2则可抑制CRF引起的细胞通透性增加。Toll样受体4（TLR 4）拮抗剂阿曲库他仑或白细胞介素1受体拮抗剂阿那白滞素（anakinra）可阻断CRF引起的内脏异常性疼痛和肠道通透性增加。皮下注射脂多糖（免疫应激）或重复避水应激（WAS，心理应激），每天1小时，持续3天诱导内脏异常性疼痛和肠道通透性增加（动物IBS模型），这也被阻断astressin，eritoran或阿那白滞素。总之，应激诱导的内脏异常性疼痛和结肠通透性增加是通过外周CRF受体介导的。CRF通过TLR 4和细胞因子系统诱导这些内脏变化，这些变化是CRF 1依赖的，CRF 2的激活抑制了这些CRF 1触发的反应。CRF可能通过调节免疫系统而改变内脏的变化，这些变化被认为是IBS的重要病理生理机制。
Visceral allodynia and increased colonic permeability are considered to be crucial pathophysiology of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and immune-mediated mechanisms have been proposed to contribute to these changes in IBS, but the precise roles have not been determined. We explored these issues in rats in vivo. The threshold of visceromotor response, i.e., abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal injection of CRF increased the permeability, which was blocked by astressin, a non-selective CRF receptor antagonist, but astressin(2)-B, a selective CRF receptor subtype 2 (CRF2) antagonist did not modify it. Urocortin 2, a selective CRF2 agonist inhibited the increased permeability by CRF. Eritoran, a toll-like receptor 4 (TLR4) antagonist or anakinra, an interleukin-1 receptor antagonist blocked the visceral allodynia and the increased gut permeability induced by CRF. Subcutaneous injection of lipopolysaccharide (immune stress) or repeated water avoidance stress (WAS, psychological stress), 1 h daily for 3 days induced visceral allodynia and increased gut permeability (animal IBS models), which were also blocked by astressin, eritoran or anakinra. In conclusion, stress-induced visceral allodynia and increased colonic permeability were mediated via peripheral CRF receptors. CRF induced these visceral changes via TLR4 and cytokine system, which were CRF1 dependent, and activation of CRF2 inhibited these CRF1-triggered responses. CRF may modulate immune system to alter visceral changes, which are considered to be pivotal pathophysiology of IBS.