Glowka T R, Steinebach A, Stein K, Schwandt T, Lysson M, Holzmann B, Tsujikawa K, de Jonge W J, Kalff J C, Wehner S
Department of Surgery, University of Bonn, Bonn, Germany.
Department of Surgery, Technical University Munich, Munich, Germany.
Neurogastroenterol Motil. 2015 Jul;27(7):1038-49. doi: 10.1111/nmo.12584. Epub 2015 Apr 30.
Abdominal surgery results in neuronal mediator release and subsequent acute intestinal hypomotility. This phase is followed by a longer lasting inflammatory phase resulting in postoperative ileus (POI). Calcitonin gene-related peptide (CGRP) has been shown to induce motility disturbances and in addition may be a candidate mediator to elicit neurogenic inflammation. We hypothesized that CGRP contributes to intestinal inflammation and POI.
The effect of CGRP in POI was tested in mice treated with the highly specific CGRP receptor antagonist BIBN4096BS and in CGRP receptor-deficient (RAMP-1(-/-) ) mice. POI severity was analyzed by cytokine expression, muscular inflammation and gastrointestinal (GI) transit. Peritoneal and muscularis macrophages and mast cells were analyzed for CGRP receptor expression and functional response to CGRP stimulation.
Intestinal manipulation (IM) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin (IL)-6 and IL-1β transcription and leukocyte infiltration in the muscularis externa and increased GI transit time. CGRP potentiates IM-induced cytokine transcription within the muscularis externa and peritoneal macrophages. BIBN4096BS reduced cytokine levels and leukocyte infiltration and normalized GI transit. RAMP1(-/-) mice showed a significantly reduced leukocyte influx. CGRP receptor was expressed in muscularis and peritoneal macrophages but not mast cells. CGRP mediated macrophage activation but failed to induce mast cell degranulation and cytokine expression.
CONCLUSIONS & INFERENCES: CGRP is immediately released during abdominal surgery and induces a neurogenic inflammation via activation of abdominal macrophages. BIBN4096BS prevented IM-induced inflammation and restored GI motility. These findings suggest that CGRP receptor antagonism could be instrumental in the prevention of POI.
腹部手术会导致神经介质释放，随后出现急性肠道运动减弱。此阶段之后是持续时间更长的炎症阶段，导致术后肠梗阻（POI）。降钙素基因相关肽（CGRP）已被证明可诱发运动障碍，此外可能是引发神经源性炎症的候选介质。我们推测CGRP会导致肠道炎症和POI。
在使用高度特异性CGRP受体拮抗剂BIBN4096BS处理的小鼠以及CGRP受体缺陷（RAMP-1(-/-)）小鼠中测试CGRP在POI中的作用。通过细胞因子表达、肌肉炎症和胃肠（GI）转运来分析POI的严重程度。分析腹膜和肌层巨噬细胞以及肥大细胞的CGRP受体表达和对CGRP刺激的功能反应。
肠道操作（IM）导致肌间神经释放CGRP，并同时增加白细胞介素（IL）-6和IL-1β转录以及肌层中白细胞浸润，并增加GI转运时间。CGRP增强IM诱导的肌层和腹膜巨噬细胞内细胞因子转录。BIBN4096BS降低细胞因子水平和白细胞浸润，并使GI转运正常化。RAMP1(-/-)小鼠的白细胞流入明显减少。CGRP受体在肌层和腹膜巨噬细胞中表达，但在肥大细胞中未表达。CGRP介导巨噬细胞活化，但未能诱导肥大细胞脱颗粒和细胞因子表达。
腹部手术期间CGRP立即释放，并通过激活腹部巨噬细胞诱导神经源性炎症。BIBN4096BS可预防IM诱导的炎症并恢复GI动力。这些发现表明CGRP受体拮抗作用可能有助于预防POI。
