Microangiopathy triggers, and inducible nitric oxide synthase exacerbates dextran sulfate sodium-induced colitis
Microangiopathy triggers, and inducible nitric oxide synthase exacerbates dextran sulfate sodium-induced colitis
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DOI：
10.1038/labinvest.2015.60
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发表时间：
2015-07-01
影响因子：
5
通讯作者：
Hashimoto, Hisashi
中科院分区：
文献类型：
--
作者：
Saijo, Hiroki;Tatsumi, Norifumi;Hashimoto, Hisashi
溃疡性结肠炎（UC）是炎症性肠病的代表性临床表现，可引起慢性胃肠道炎症。右旋糖酐硫酸钠（DSS）诱导的结肠炎小鼠已用于研究UC发病机制，在该UC模型中，据报道粘膜上皮的干扰和损伤会导致结肠炎。然而，DSS如何零星地分解上皮仍不清楚。在本研究中，我们着重于DSS诱导的结肠炎的结肠微循环和肌间神经元。此外，我们研究了肌间神经元作为预防结肠炎恶化的靶点的潜力。荧光血管造影和组织病理学研究表明，DSS管理引起血管破裂上皮疾病出现之前。随着结肠炎的加重，固有层的缺血条件诱导了肌间神经元中诱导型一氧化氮合酶（iNOS）的表达。当神经元活性被丁基东莨菪碱抑制时，神经元iNOS表达下降，并且结肠炎的恶化被阻止。这些结果表明DSS诱导的结肠炎是由粘膜微循环障碍触发的，过度的神经元兴奋加重了结肠炎。在人类UC的缓解期，结肠微循环的内窥镜检查可以使疾病复发的早期检测，和神经元iNOS表达的抑制可以防止疾病恶化。
Ulcerative colitis (UC) is a representative clinical manifestation of inflammatory bowel disease that causes chronic gastrointestinal tract inflammation. Dextran sulfate sodium (DSS)-induced colitis mice have been used to investigate UC pathogenesis, and in this UC model, disturbance and impairment of the mucosal epithelium have been reported to cause colitis. However, how DSS sporadically breaks down the epithelium remains unclear. In this study, we focused on the colonic microcirculation and myenteric neurons of DSS-induced colitis. Moreover, we examined the potential of myenteric neurons as a target to prevent exacerbation of colitis. Fluorescent angiographic and histopathological studies revealed that DSS administration elicited blood vessel disruption before epithelial disorders appeared. Ischemic conditions in the lamina propria induced inducible nitric oxide synthase (iNOS) expression in myenteric neurons as colitis aggravated. When neuronal activity was inhibited with butylscopolamine, neuronal iNOS expression decreased, and the exacerbation of colitis was prevented. These results suggested that DSS-induced colitis was triggered by microcirculatory disturbance in the mucosa, and that excessive neuronal excitation aggravated colitis. During remission periods of human UC, endoscopic inspection of the colonic microcirculation may enable the early detection of disease recurrence, and inhibition of neuronal iNOS expression may prevent the disease from worsening.