MECHANISMS OF PROSTAGLANDIN INDUCED INTESTINAL REPAIR

前列腺素诱导的肠道修复机制

• 批准号: 6523696
• 负责人: ANTHONY BLIKSLAGER
• 金额: $ 10.82万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-05 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523696
• 关键词: calcium flux; calcium indicator; cyclic AMP; electrophysiology; enzyme mechanism; fibroblasts; gastrointestinal absorption /transport; gastrointestinal epithelium; hormone regulation /control mechanism; immunocytochemistry; intestine disorder; ischemia; laboratory rat; membrane potentials; paracrine; prostaglandin E; prostaglandin endoperoxide synthase; prostaglandins; swine; tight junctions; tissue /cell culture

The long range goal of this research program is to study mechanisms responsible for maintenance and restoration of the intestinal barrier. Intestinal ischemia/reperfusion injury is characterized by acute breakdown of the intestinal barrier. However, preliminary studies indicate that prostaglandins signal a remarkably rapid recovery of epithelial barrier function via the second messengers Ca2+ and cyclic AMP. Our central hypothesis is that prostaglandins I2 and E2 (PGI2 and PGE2) are elaborated by cyclooxygenase-2 (COX-2) during intestinal injury from sub-epithelial fibroblasts and restore barrier function by signaling closure of inter-epithelial tight junctions. Tight junctions close in response, to a synergistic signal between intracellular and cyclic AMP, which are increased by PGI2-stimulated cholinergic nerves and PGE2 receptor-linked adenylate cyclase respectively. The aims of this research are: to determine if PGI2 and PGE2 increase transepithelial resistance in ischemic-injured epithelium by a specific action on tight junctions; to determine the neural and epithelial receptor pathways by which PGI2 and PGE2 signal recovery of transepithelial resistance; and to determine the cellular and enzymatic source of prostaglandins responsible for rescuing epithelial barrier function. Two distinct injury models will be used: ischemic-injured intestinal mucosa and oxidant-damaged epithelial monolayers. Tissues will be mounted in Ussing chambers, and transepithelial electrical resistance will be monitored as an indicator of epithelial integrity. Radio-labeled fluxes will be used to determine the contribution of tight junction closure and restitution. Mechanisms by which prostaglandins signal repair will be tested by measuring second messengers and by blocking epithelial and neural signaling pathways. The cellular source of reparative prostaglandins will be determined by immunohistochemistry and fibroblast monolayer studies. Inhibition of COX-2 will be used to determine the contribution of distinct cyclooxygenases in the repair response. These experiments will provide insight into the signaling pathways and mechanisms by which prostaglandins trigger repair of acutely-injured intestinal epithelium.

这项研究计划的长期目标是研究 负责维持和恢复肠道屏障。 肠缺血/再灌注损伤的特征在于急性肠缺血/再灌注损伤。 肠道屏障破裂。然而，初步研究 这表明，三尖杉脂素信号， 上皮屏障功能通过第二信使钙离子和环 风机放大器 我们的中心假设是，E2和I2（PGI 2和E2）可能与前列腺素（PGI 2）有关。 PGE 2）在肠内代谢过程中被环氧合酶-2（考克斯-2）加工 并恢复屏障功能 上皮间紧密连接的信号关闭。 紧密连接 在响应中接近于细胞内和细胞外之间的协同信号， 环AMP，其由PGI 2刺激的胆碱能神经增加 和PGE 2受体连接的腺苷酸环化酶。 的目的 这项研究是：确定是否PGI 2和PGE 2增加 一种特异性的免疫抑制剂对缺血损伤上皮细胞跨上皮电阻的影响 对紧密连接的作用;以确定神经和上皮 PGI 2和PGE 2信号恢复的受体途径 跨上皮电阻;并确定细胞和酶 负责拯救上皮屏障的胰高血糖素来源 功能 将使用两种不同的损伤模型： 肠粘膜和氧化损伤的上皮单层。 组织 将被安装在Ussing室中，并且经上皮电 将监测阻力作为上皮完整性的指标。 放射性标记的通量将被用来确定紧密的贡献 连接关闭和恢复。 芦荟素的作用机制 信号修复将通过测量第二信使和 阻断上皮细胞和神经信号通路。 细胞来源 将通过免疫组织化学测定修复性前列腺素 和成纤维细胞单层研究。 考克斯-2的抑制将用于 确定不同的环氧合酶在修复中的作用 反应这些实验将提供深入了解信号 途径和机制，通过这些途径和机制， 严重损伤的肠上皮