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.

严重创伤后发生多器官功能障碍综合征(MODS)是很常见的，尤其是当患者出现休克、代谢性酸中毒和需要多次输注压缩的红血时。出血和创伤后MODS的发展明显与由此引起的全身炎症反应的大小有关。因此，研究人员投入了大量的精力来了解更多关于各种信号的信息 创伤/出血后导致先天免疫系统激活和促炎介质形成的途径。虽然仍有很多东西需要了解，但许多关键信号通路的重要成分已经被阐明。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的组织病理学明显平淡无奇；无论是由于坏死还是细胞凋亡，大量细胞死亡几乎肯定不是MODS的原因。相反，MODS发展的最后一步可能是由于控制不良的全身炎症的有害影响，多个器官中广泛存在的实质细胞功能障碍。 回应。因此，一个极未被探索的研究领域可以用这个问题来概括：创伤后炎症反应的调节失调是如何导致实质细胞功能障碍的？基于我们在前一个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，我们假设创伤后多器官功能障碍综合征的结果，至少部分是由于在表达和亚细胞定位方面的扰动 多种上皮组织中的紧密连接(TJ)蛋白，如肺、肝和肠道中发现的那些。由于与其他组织相比，研究肠粘膜上皮性TJ功能相对容易，我们的努力将集中在肠道上，尽管关键发现将通过开展实验来研究其他器官(即肝脏和肺)的上皮性TJ功能而得到证实。工作将在这些目标下组织起来。(1)：检验假设 失血性休克/复苏(HS/R)通过依赖于一氧化氮、活性氧和/或过氧亚硝酸盐的形成机制，导致多层上皮细胞TJ结构和功能的改变。(2)验证HS/R引起的肠道、肝脏和肺上皮细胞TJ结构和功能紊乱的假设，至少部分是通过HMGB 1和/或其他相关配体与晚期糖基化终产物受体结合而介导的。 (3)验证IL-6是HS/R所致肠、肝、肺上皮细胞结构和功能紊乱的关键介质的假说。(4)验证及时应用烟酰胺腺嘌呤二核苷酸(NAD+)可改善HS/R引起的肠、肺、肝上皮功能障碍的假说。