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.
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