Clayburgh Daniel R, Shen Le, Turner Jerrold R
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Lab Invest. 2004 Mar;84(3):282-91. doi: 10.1038/labinvest.3700050.
A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the interstitium. This intestinal barrier is compromised in a number of intestinal diseases, most notably inflammatory bowel disease. In vitro studies have demonstrated that cytokines elaborated by immune cells can cause the mucosal barrier to become leaky; these cytokines are known to be increased in intestinal mucosa involved in inflammatory bowel disease. Detailed information describing the mechanisms by which altered cytokine signaling occurs is not available, but recent data implicate the cytoskeleton within epithelial cells as a critical regulator of the mucosal barrier under physiological and pathophysiological conditions. Using available data, we describe a model of intestinal disease where an initial insult to the epithelial barrier may trigger a self-amplifying cycle of immune activation, cytokine release, and further barrier dysfunction. This model is supported by the observation that pharmacological abrogation of cytokine signaling corrects both barrier defects and clinical disease in animal models and human patients, although such therapy clearly has multiple mechanisms. Other therapeutic targets that represent strategies to prevent or reverse disease processes are also considered. The overarching hypothesis is that modulation of the mucosal epithelial barrier plays a critical role in the initiation and propogation of inflammatory intestinal diseases.
肠黏膜的一项关键功能是形成一道将肠腔内容物与间质分隔开来的屏障。在许多肠道疾病中，尤其是炎症性肠病，这道肠道屏障会受到损害。体外研究表明，免疫细胞分泌的细胞因子可导致黏膜屏障渗漏；已知这些细胞因子在参与炎症性肠病的肠黏膜中会增加。目前尚无关于细胞因子信号传导改变发生机制的详细信息，但最近的数据表明，上皮细胞内的细胞骨架在生理和病理生理条件下是黏膜屏障的关键调节因子。利用现有数据，我们描述了一种肠道疾病模型，其中上皮屏障的初始损伤可能引发免疫激活、细胞因子释放和进一步屏障功能障碍的自我放大循环。这一模型得到了以下观察结果的支持：在动物模型和人类患者中，细胞因子信号传导的药理学消除可纠正屏障缺陷和临床疾病，尽管这种治疗显然有多种机制。还考虑了代表预防或逆转疾病进程策略的其他治疗靶点。总的假设是，黏膜上皮屏障的调节在炎症性肠病的发生和发展中起关键作用。
