Fujino Kazunori, Takami Yoji, de la Fuente Sebastian G, Ludwig Kirk A, Mantyh Christopher R
Department of General Surgery, Duke University Medical Center, Durham, NC 27710, USA.
J Gastrointest Surg. 2004 Nov;8(7):842-7; discussion 847-8. doi: 10.1016/j.gassur.2004.07.011.
Primary sensory neurons are important in regard to the initiation and propagation of intestinal inflammation. The vanilloid receptor subtype-1 (VR-1) is a cation channel located on the sensory nerves that, when stimulated, release proinflammatory peptides. Previous reports have indicated that inhibition of VR-1 with capsazepine (CPZ), a VR-1 antagonist, attenuates dextran sodium sulfate (DSS) colitis in rats. DSS-induced colitis resembles ulcerative colitis with regard to its pathologic features. In this study, we examined the effect of CPZ on trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model of intestinal inflammation that most closely resembles the histologic and microscopic features of Crohn's disease. Colitis was induced by administering a single enema of 100 mg/kg TNBS in 50% ethanol via catheter to lightly anesthetized rats. Subsets of rats were treated with either 1 micromol/kg/ml of CPZ or CPZ-vehicle via enema for 6 days. Seven days after TNBS administration, rats were sacrificed and inflammation was assessed using a validated macroscopic damage score (MDS) and by measuring myeloperoxidase (MPO) activity. In addition, histologic examination was performed. TNBS administration resulted in reproducible chronic erosive lesions extending into the muscularis propria and extensive recruitment of neutrophils in the distal colon. MDS and MPO scores were considerably elevated in the TNBS colons when compared with the TNBS vehicle animals. TNBS rats treated with CPZ enemas exhibited a substantial reduction in MDS and MPO scores and demonstrated dramatically improved pathologic findings. Topical CPZ resulted in considerable attenuation of TNBS-induced colitis. These results support the role of VR-1 and sensory neurons with regard to intestinal inflammation.
初级感觉神经元在肠道炎症的起始和传播方面起着重要作用。香草酸受体亚型1（VR-1）是一种位于感觉神经上的阳离子通道，受到刺激时会释放促炎肽。先前的报道表明，用VR-1拮抗剂辣椒素（CPZ）抑制VR-1可减轻大鼠的葡聚糖硫酸钠（DSS）结肠炎。DSS诱导的结肠炎在病理特征上类似于溃疡性结肠炎。在本研究中，我们研究了CPZ对三硝基苯磺酸（TNBS）诱导的结肠炎的影响，TNBS诱导的结肠炎是一种肠道炎症实验模型，与克罗恩病的组织学和显微镜特征最为相似。通过导管向轻度麻醉的大鼠单次灌肠100mg/kg TNBS溶于50%乙醇中来诱导结肠炎。部分大鼠通过灌肠接受1μmol/kg/ml的CPZ或CPZ赋形剂治疗6天。给予TNBS 7天后，处死大鼠，使用经过验证的宏观损伤评分（MDS）并通过测量髓过氧化物酶（MPO）活性来评估炎症。此外，还进行了组织学检查。给予TNBS导致可重现的慢性糜烂性病变延伸至固有肌层，并在远端结肠大量募集中性粒细胞。与TNBS赋形剂处理的动物相比，TNBS结肠中的MDS和MPO评分显著升高。接受CPZ灌肠治疗的TNBS大鼠的MDS和MPO评分大幅降低，病理结果显著改善。局部应用CPZ可显著减轻TNBS诱导的结肠炎。这些结果支持了VR-1和感觉神经元在肠道炎症中的作用。
