S-nitrosoglutathione regulation of intestinal barrier function in Crohn's disease

描述(申请人提供)：尽管进行了广泛的研究，克罗恩炎症性肠病的病因仍不清楚，可能的建议归因于遗传易感性、感染性因素、免疫功能障碍和各种环境因素。许多临床研究表明，克罗恩病患者及其一级亲属的肠道通透性增加。粘膜通透性增强也是疾病复发的预测因素。因此，肠道屏障功能的原发障碍构成了发病机制中的一个潜在的疾病因素。我们已经确定了一种新的肠道通透性的动态平衡调节因子，它是由肠神经胶质细胞主动产生和分泌的。我们认为，S-亚硝基谷胱甘肽通过反硝化上皮紧密连接相关蛋白来调节肠屏障功能。转亚硝化是一种类似于蛋白质磷酸化和乙酰化的信号转译后修饰机制。我们推测，异常的S-亚硝基谷胱甘肽稳态构成了克罗恩病导致肠屏障功能障碍的发病机制。我们的初步发现支持这一观点，即S-亚硝基谷胱甘肽在克罗恩病患者的活检组织中恢复了肠屏障功能，但在没有炎症性肠病的对照患者中没有恢复。S-亚硝基谷胱甘肽是一种神经胶质衍生的小分子，可保护上皮屏障的完整性，这代表着对肠道屏障功能背后的细胞相互作用的理解取得了重大进展。这些发现可能有助于开发与炎性屏障功能障碍相关的病理疾病的新疗法，如克罗恩病。公共卫生相关性：跨越上皮和内皮细胞的屏障功能对于动态平衡的组织调节至关重要。我们确定S-亚硝基谷胱甘肽是一种新的肠屏障功能调节剂。我们推测，S-亚硝基谷胱甘肽的异常稳态构成了克罗恩病的一种新的发病机制。我们计划调查这一发现是否为炎症性通透性障碍的治疗提供了一种新的方法。

DESCRIPTION (provided by applicant): Despite extensive research, the etiology of Crohn's inflammatory bowel disease remains unknown with possible suggestions attributed to genetic susceptibility, infectious agents, immune dysfunction, and various environmental agents. A number of clinical studies have demonstrated an increased intestinal permeability in Crohn's disease patients and in their first-degree relatives. Enhanced mucosal permeability is also a predictive factor of disease recurrence. Thus, a primary disorder of intestinal barrier function constitutes a potential disease factor in the pathogenesis. We have identified a novel homeostatic regulator of intestinal permeability that is actively produced and secreted by enteric glial cells. We propose that s-nitrosoglutathione regulates intestinal barrier function via transnitrosylation of epithelial tight-junction associated proteins. Transnitrosylation is a signaling mechanism involving post-translational modification analogous to protein phosphorylation and acetylation. We hypothesize that aberrant s-nitrosoglutathione homeostasis constitutes a disease mechanism in Crohn's disease resulting in intestinal barrier dysfunction. This view is supported by our preliminary findings that s-nitrosoglutathione restores intestinal barrier function in biopsies from Crohn's disease patients but not in control patients without inflammatory bowel disease. The identification of s-nitrosoglutathione as a glial-derived, small, soluble molecule that protects epithelial-barrier integrity represents a significant advance in the understanding of the cellular interactions that underlie intestinal barrier function. These findings may help in the development of novel therapies for pathologies, such as Crohn's disease, that are associated with inflammatory barrier dysfunction. PUBLIC HEALTH RELEVANCE: Barrier functions across epithelia and endothelia are essential for homeostatic tissue regulation. We identified s-nitrosoglutathione as a novel regulator of intestinal barrier function. We hypothesize that aberrant homeostasis of s-nitrosoglutathione constitutes a new disease mechanism in Crohn's disease. We plan to investigate whether this finding offers a novel approach to therapy for inflammatory permeability disorders.