The novel CGRP receptor antagonist BIBN4096BS alleviates a postoperative intestinal inflammation and prevents postoperative ileus
The novel CGRP receptor antagonist BIBN4096BS alleviates a postoperative intestinal inflammation and prevents postoperative ileus
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DOI：
10.1111/nmo.12584
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发表时间：
2015-07-01
影响因子：
3.5
通讯作者：
Wehner, S.
中科院分区：
文献类型：
--
作者：
Glowka, T. R.;Steinebach, A.;Wehner, S.
背景腹部手术导致神经介质释放和随后的急性肠道蠕动低下。此阶段之后是更持久的炎症阶段，导致术后肠梗阻 (POI)。降钙素基因相关肽（CGRP）已被证明可诱导运动障碍，此外可能是引发神经源性炎症的候选介质。我们假设 CGRP 会导致肠道炎症和 POI。方法 在用高度特异性 CGRP 受体拮抗剂 BIBN4096BS 治疗的小鼠和 CGRP 受体缺陷 (RAMP-1(-/-)) 小鼠中测试 CGRP 对 POI 的影响。通过细胞因子表达、肌肉炎症和胃肠道 (GI) 转运来分析 POI 严重程度。分析腹膜和肌层巨噬细胞和肥大细胞的 CGRP 受体表达和对 CGRP 刺激的功能反应。主要结果 肠操作 (IM) 导致肌间神经释放 CGRP，同时增加白细胞介素 (IL)-6 和 IL-1 β 转录以及外肌层白细胞浸润，并增加胃肠道转运时间。 CGRP 增强 IM 诱导的外肌层和腹膜巨噬细胞内细胞因子的转录。 BIBN4096BS 降低细胞因子水平和白细胞浸润并使胃肠道运输正常化。 RAMP1(-/-) 小鼠表现出白细胞流入显着减少。 CGRP 受体在肌层和腹膜巨噬细胞中表达，但在肥大细胞中不表达。 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。结论与推论 CGRP 在腹部手术期间立即释放，并通过激活腹部巨噬细胞诱导神经源性炎症。 BIBN4096BS 可预防 IM 诱发的炎症并恢复胃肠道蠕动。这些发现表明 CGRP 受体拮抗作用可能有助于预防 POI。
Background 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. Methods 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. Key Results Intestinal manipulation (IM) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin (IL)-6 and IL-1 beta 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.