BQ788 揭示神经胶质 ET 受体调制对神经元胆碱能和氮能通路的抑制作用，从而抑制肠道运动：与术后肠梗阻有关。
BQ788 reveals glial ET receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus.
机构信息
Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
Department of Physiology, Michigan State University, East Lansing, Michigan, USA.
出版信息
Br J Pharmacol. 2023 Oct;180(19):2550-2576. doi: 10.1111/bph.16145. Epub 2023 Jun 25.
BACKGROUND AND PURPOSE
ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET signalling regulates neural-motor pathways of intestinal motility and inflammation.
EXPERIMENTAL APPROACH
We studied ET signalling using: ET drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K -depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10 ;Rpl22-HAflx or ChAT ;Rpl22-HAflx mice, Sox10 ::GCaMP5g-tdT, Wnt1 ::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation.
KEY RESULTS
In the muscularis externa ET receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ET receptor modulation of Ca waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca waves and prevent BQ788 amplification of contractions. The ET receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET up-regulation, SaTX-hypersensitivity and glial amplification of ET signalling. In vivo BQ788 (i.p., 1 mg·kg ) attenuates intestinal inflammation in POI.
CONCLUSION AND IMPLICATIONS
Enteric glial ET-1/ET signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI.
背景与目的
内皮素-1（ET-1）信号调节肠道蠕动和炎症，但 ET-1/ET 受体信号的作用知之甚少。肠胶质细胞调节正常的蠕动和炎症。我们研究了胶质细胞 ET 信号是否调节肠道蠕动和炎症的神经-运动途径。
实验方法
我们使用以下方法研究 ET 信号：ET 药物（ET-1、SaTX、BQ788）、神经元活性依赖性刺激（高 K-去极化、EFS）、神经胶质毒素、Tg（Ednrb-EGFP）EP59Gsat/Mmucd 小鼠、Sox10 中的细胞特异性 mRNA；Rpl22-HAflx 或 ChAT；Rpl22-HAflx 小鼠、Sox10::GCaMP5g-tdT、Wnt1::GCaMP5g-tdT 小鼠、肌肉张力记录、流体诱导蠕动、ET-1 表达、qPCR、western blot、3-D LSM-免疫荧光共标记研究在 LMMP-CM 和术后肠梗阻（POI）的肠道炎症模型中。
主要结果
在肌层外，ET 受体仅在胶质细胞中表达。ET-1 在 RiboTag（ChAT）-神经元、分离的神经节和神经节内的曲张神经纤维中表达，与周围蛋白或 SP 共标记。ET-1 释放提供了活动依赖性的胶质细胞 ET 受体调制，在神经诱发的胶质细胞反应中引起 Ca 波。BQ788 揭示了胶质细胞和神经元 Ca 反应以及兴奋性胆碱能收缩的放大，对 L-NAME 敏感。神经胶质毒素破坏 SaTX 诱导的胶质细胞 Ca 波，并防止 BQ788 对收缩的放大。ET 受体与收缩和蠕动的抑制有关。炎症导致胶质细胞 ET 上调、SaTX 超敏和 ET 信号的胶质细胞放大。体内 BQ788（腹腔内，1mg·kg）减轻 POI 中的肠道炎症。
结论和意义
肠胶质细胞 ET-1/ET 信号提供了对神经-运动回路的双重调节，以抑制蠕动。它抑制兴奋性胆碱能并刺激抑制性氮能运动途径。胶质细胞 ET 受体的放大与肌层外炎症和可能的 POI 发病机制有关。
Zotero 插件