Preservation of mucosal barrier in surgical diseases

描述(由申请人提供)： 肠损伤和粘膜屏障破坏在外科手术、小肠移植和烧伤后感染性休克和多器官功能障碍综合征的发生发展中起重要作用。因此，我们的长期目标是研究外科疾病中粘膜屏障的保护机制。我们和其他人发现TFF3(三叶因子3)对急性粘膜损伤具有保护作用。然而，TFF3诱导粘膜保护的机制尚不清楚。最近，我们发现TFF3在一过性事件中诱导肠道内核因子-K：B的激活。目前，对瞬时激活的核因子-kappaB在体内的生理作用知之甚少，尽管核因子-kappaB的长时间激活在炎症的发生中起着重要作用。一些证据表明，核因子-kappaB的瞬时激活导致(A)细胞保护和抗凋亡分子的上调，这些分子可以保护细胞免受急性细胞损伤；(B)核因子-kappaB途径的抑制分子，从而减弱组织中炎症网络的放大。因此，我们假设TFF3在炎症攻击之前对肠上皮细胞中的NF-kappaB的瞬时激活在TFF3诱导的粘膜保护中起着核心作用。在初步研究中，我们已经(A)确定了TFF3触发的NF-kappaB的瞬时激活和TFF3诱导的粘膜保护之间的直接联系；以及(B)发现用TFF3预处理肠上皮细胞加强了NF-kappaB的负调控循环，限制了对促炎细胞因子刺激的炎症反应。在这项提案中，我们将解决以下三个合乎逻辑的问题：(A)TFF3诱导的肠上皮细胞中NF-kappaB的瞬时激活在TFF3的预防作用中是否发挥重要作用？(B)TFF3是否需要NF-kappaB来调控肠上皮细胞中肠道保护性基因的表达？这些基因表达的调控机制是什么？(C)TFF3如何在肠上皮细胞中诱导核因子-kappaB的瞬时激活？该提议的实现将提供一个新的概念，即在肠道上皮细胞炎症发生之前瞬时激活核因子-KB在保护粘膜屏障方面发挥着重要作用。我们希望这项研究将为制定在手术条件下保护粘膜屏障和预防危重疾病的策略提供帮助。

DESCRIPTION (provided by applicant): Gut injury and mucosal barrier failure play an important role in the development of septic shock and multiple organ dysfunction syndrome after surgical procedures, small bowel transplantation, and burns. Thus, our long term objective is to study mechanisms of preservation of mucosal barrier in surgical disorders. We and others found that TFF3 (trefoil factor 3) protects against acute mucosal injury. However, the mechanisms through which TFF3 induces mucosal protection are not clear. Recently, we found that TFF3 induces activation of intestinal NF-K:B in a transient event. Currently, relatively little is known about the physiological role of transient activated NF-KappaB in vivo although the prolonged activation of NF-KappaB plays an important role in the onset of inflammation. Several lines of evidence suggest that transient activation of NF-KappaB results in up-regulation of (a) cytoprotective and anti-apoptotic molecules, which protect against acute cellular injuries; and (b) inhibitory molecules of the NF-KappaB pathway, which subsequently attenuate amplification of the inflammatory network in tissues. Thus, we hypothesize that transient activation of NF-KappaB in intestinal epithelial cells by TFF3 prior to inflammatory strikes plays a central role in TFF3-induced mucosal protection. In preliminary studies, we have (a) determined the direct link between TFF3-triggered transient activation of NF-kappaB and TFF3-induced mucosal protection; and (b) found that pretreatment of intestinal epithelial cells with TFF3 reinforces the negative regulatory loop of NF-KappaB and limits inflammatory response to proinflammatory cytokine stimulations. In this proposal, we will address the following three logical questions: (a) Does TFF3-induced transient activation of NF-KappaB in intestinal epithelium play an essential role in the preventive effect of TFF3? (b) Is NF-KappaB required for TFF3 to regulate expression of gut-protective genes in intestinal epithelial cells and which mechanisms are involved in regulation of these gene expressions? (c) How does TFF3 induce transient activation of NF-KappaB in the intestinal epithelium? Achievement of the proposal will provide a novel concept that transient activation of NF-KB prior to the onset of inflammations in intestinal epithelium plays an important role in preservation of the mucosal barrier. We hope the study will shed the light for development of strategies to preserve mucosal barrier and prevent critical illnesses during surgical conditions.