MOLECULAR BASIS FOR EPITHELIAL BARRIER DYSFUNCTION/PROJECT 2

上皮屏障功能障碍的分子基础/项目 2

• 批准号: 6829217
• 负责人: Mitchell P. Fink
• 金额: $ 21.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829217
• 关键词: biological signal transduction; free radical oxygen; gastrointestinal system; gene targeting; genetically modified animals; glycation; hemorrhagic shock; inflammation; injury; interleukin 6; intestinal mucosa; laboratory mouse; liver; lung; monoclonal antibody; multiple organ failure; nicotinamide adenine dinucleotide; nitric oxide; nonhistone nucleoprotein; peroxynitrites; protein localization; protein structure function; resuscitation; stress; tight junctions; trauma

Development of the multiple organ dysfunction syndrome (MODS) is a common after severe trauma, particularly when patients develop shock, metabolic acidosis, and require multiple transfusions of packed red blood. The development of MODS after hemorrhage and trauma clearly is related to the magnitude of the resulting systemic inflammatory response. Accordingly, investigators have invested a great deal of effort to learn more about various signaling pathways that lead to the activation of the innate immune system and the elaboration of pro-inflammatory mediators after trauma/hemorrhage. Although a great deal remains to be learned, important elements of many of the key signaling pathways already have been elucidated. In contrast, the biochemical and cell biological underpinnings for post-traumatic organ dysfunction per se remain very poorly understood. It is known, however, that the histopathology of MODS in humans is remarkably bland; massive cell death, whether due to necrosis or apoptosis, is almost certainly not the cause of MODS. Rather, the final step in the development of MODS is probably the widespread dysfunction of parenchymal cells in multiple organs as a result of the deleterious effects of a poorly controlled systemic inflammatory response. Thus, a hugely under-explored area of research can be summarized by this question: How does post-traumatic dysregulation of the inflammatory response lead to parenchymal cell dysfunction? Based on our work during the previous cycle of funding of this grant as well as other work performed recently by our research group, we hypothesize that post-traumatic MODS results, at least in part, from perturbations in the expression and subcellular localization of tight junction (TJ) proteins in multiple epithelial tissues, such as those found in the lung, liver and gut. Because it is relatively easier to investigate epithelial TJ function in the intestinal mucosa than it is in other tissues, our efforts will focus on the gut, although key findings will be corroborated by carrying out experiments to study epithelial TJ function in other organs (i.e., the liver and lungs). The work will be organized under these Aims. (1): Test the hypothesis that hemorrhagic shock/resuscitation (HS/R) in mice leads to alterations in TJ structure and function in multiple epithelia via mechanisms that depend on the formation of nitric oxide, reactive oxygen species, and/or peroxynitrite. (2) Test the hypothesis that HS/R-induced derangements in gut, liver and lung epithelial TJ structure and function are mediated, at least, in part by binding of HMGB 1 and/or other related ligands to the receptor for advanced glycation end-products. (3) Test the hypothesis that IL-6 is a key mediator of HS/R-induced derangements in gut, liver and pulmonary epithelial TJ structure and function. (4) Test the hypothesis that timely treatment with nictoninamide adenine dinucleotide (NAD +) can ameliorate HS/R-induced alterations in gut, lung, and liver epithelial dysfunction.

多器官功能障碍综合征 (MODS) 的发生在严重创伤后很常见，特别是当患者出现休克、代谢性酸中毒并需要多次输注浓缩红血时。出血和创伤后MODS的发展显然与由此产生的全身炎症反应的程度有关。因此，研究人员投入了大量的精力来更多地了解各种信号传导 导致先天免疫系统激活和创伤/出血后促炎介质产生的途径。尽管还有很多东西有待了解，但许多关键信号传导途径的重要元素已经被阐明。相比之下，创伤后的生化和细胞生物学基础 器官功能障碍本身仍然知之甚少。然而，众所周知，人类 MODS 的组织病理学非常温和。大量细胞死亡，无论是由于坏死还是凋亡，几乎可以肯定不是 MODS 的原因。相反，MODS 发展的最后一步可能是由于全身炎症控制不良的有害影响，导致多个器官的实质细胞广泛功能障碍。 回复。因此，一个尚未充分探索的研究领域可以通过这个问题来总结：创伤后炎症反应失调如何导致实质细胞功能障碍？根据我们在上一资助周期中的工作以及我们的研究小组最近进行的其他工作，我们假设创伤后 MODS 至少部分是由表达和亚细胞定位的扰动造成的 多个上皮组织中的紧密连接 (TJ) 蛋白，例如肺、肝和肠道中的紧密连接蛋白。由于研究肠粘膜中的上皮 TJ 功能比研究其他组织中的上皮 TJ 功能相对容易，因此我们的努力将集中在肠道上，尽管关键发现将通过研究其他器官中的上皮 TJ 功能的实验来证实（即，肝脏和肺）。这项工作将根据这些目标进行组织。 (1): 检验假设 小鼠失血性休克/复苏（HS/R）通过依赖于一氧化氮、活性氧和/或过氧亚硝酸盐形成的机制导致多个上皮细胞中 TJ 结构和功能的改变。 (2) 检验以下假设：HS/R 诱导的肠、肝和肺上皮 TJ 结构和功能紊乱至少部分是通过 HMGB 1 和/或其他相关配体与晚期糖基化末端受体的结合介导的-产品。 (3) 检验以下假设：IL-6 是 HS/R 诱导的肠道、肝脏和肺上皮 TJ 结构和功能紊乱的关键介质。 (4) 检验以下假设：及时使用烟酰胺腺嘌呤二核苷酸 (NAD +) 治疗可以改善 HS/R 诱导的肠道、肺和肝上皮功能障碍的改变。