Department of Regional Medicine and Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan; Center for Medical Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
Neuropeptides. 2022 Aug;94:102248. doi: 10.1016/j.npep.2022.102248. Epub 2022 Apr 25.
Growing evidence indicates that visceral hypersensitivity and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). In animal models, these changes are known to be mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4 (TLR4)-proinflammatory cytokine signaling. Apelin, an endogenous ligand of APJ, was reported to modulate CRF-induced enhanced colonic motility. In this context, we hypothesized that apelin also modulates visceral sensation and gut barrier, and tested this hypothesis. We measured visceral pain threshold in response to colonic balloon distention by abdominal muscle contractions assessed by electromyogram in rats. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal (ip) administration of [Ala13]-apelin-13, an APJ antagonist, blocked lipopolysaccharide (LPS)- or CRF-induced visceral hypersensitivity and colonic hyperpermeability (IBS model) in a dose-response manner. These inhibitory effects were blocked by compound C, an AMPK inhibitor, N-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor or naloxone in the LPS model. On the other hand, ip [Pyr1]-apelin-13, an APJ agonist, caused visceral hypersensitivity and colonic hyperpermeability, and these effects were reversed by astressin, a CRF receptor antagonist, TAK-242, a TLR4 antagonist or anakinra, an interleukin-1 receptor antagonist. APJ system modulated CRF-TLR4-proinflammatory cytokine signaling to cause visceral hypersensitivity and colonic hyperpermeability. APJ antagonist blocked these GI changes in IBS models, which were mediated via AMPK, NO and opioid signaling. Apelin may contribute to the IBS pathophysiology, and the inhibition of apelinergic signaling may be a promising therapeutic option for IBS.
越来越多的证据表明，内脏敏感性和肠道屏障受损在肠易激综合征（IBS）的病理生理学中起着重要作用。在动物模型中，这些变化被认为是通过促肾上腺皮质释放因子（CRF）-Toll 样受体 4（TLR4）-促炎细胞因子信号转导介导的。Apelin 是 APJ 的内源性配体，据报道可调节 CRF 诱导的增强的结肠运动。在这种情况下，我们假设 Apelin 也调节内脏感觉和肠道屏障，并对此进行了测试。我们通过肌电图评估大鼠的腹部肌肉收缩来测量对结肠球囊扩张的内脏疼痛阈值。通过量化结肠组织中吸收的 Evans 蓝来估计结肠通透性。腹腔内（ip）给予 APJ 拮抗剂[Ala13]-apelin-13，可剂量依赖性地阻断脂多糖（LPS）或 CRF 诱导的内脏敏感性和结肠高通透性（IBS 模型）。这些抑制作用可被 AMPK 抑制剂化合物 C、一氧化氮（NO）合成抑制剂 N-硝基-L-精氨酸甲酯或 LPS 模型中的纳洛酮阻断。另一方面，腹腔内给予 APJ 激动剂[Pyr1]-apelin-13 可引起内脏敏感性和结肠高通透性，这些作用可被 CRF 受体拮抗剂 astressin、TLR4 拮抗剂 TAK-242 或白细胞介素-1 受体拮抗剂 anakinra 逆转。APJ 系统调节 CRF-TLR4-促炎细胞因子信号转导以引起内脏敏感性和结肠高通透性。APJ 拮抗剂可阻断 IBS 模型中的这些胃肠道变化，这些变化是通过 AMPK、NO 和阿片样物质信号传导介导的。Apelin 可能有助于 IBS 的病理生理学，抑制 Apelin 信号可能是 IBS 的一种有前途的治疗选择。
