MOLECULAR PATHOGENESIS OF GUT INJURY IN MULTIPLE ORGAN FAILURE

多器官衰竭中肠道损伤的分子发病机制

• 批准号: 6493985
• 负责人: BRUCE C. KONE
• 金额: $ 16.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6493985
• 关键词: biological models; clinical research; gastrointestinal disorder; gastrointestinal epithelium; gene expression; human subject; laboratory rat; lipopolysaccharides; macrophage; melanocyte stimulating hormone; molecular pathology; multiple organ failure; oxidative stress; tissue /cell culture; transcription factor; trauma

Gut hypoperfusion is a common early event in trauma patients likely to progress to multiple organ failure (MOF). This ischemia/reperfusion injury precipitates a local hyperinflammatory response that likely promotes the evolution of both early and late MOF. While much is known about the pathophysiologic responses of the gut to shock and ischemia/reperfusion injury, little is known about the molecular programs induced in the gut and remote organs by these insults, or the mechanisms by which these responses may be regulated to therapeutic benefit. This project seeks to characterize these signaling events by examining the stress responses of the gut, lung, and liver in animal model of endotoxemia and mesenteric ischemia/reperfusion injury, and in cultured epithelial cells and muscularis macrophages from the small intestine. These animal and in vitro data characterize the molecular stress response of the gut, lungs, and liver in rats following lipopolysaccharide (LPS) administration and mesenteric ischemia/reperfusion. The activation and cellular distribution of stress-kinase cascades, inducible transcription factors, and their target pro-inflammatory genes will be analyzed. The molecular signaling events identified at the tissue level will be mechanistically dissected in Aim 2, using cultures of small intestinal epithelial cells and gut macrophages exposed to LPS or oxidant stress. Aim 3 will examine the effects of alpha-melanocyte stimulating hormone (alpha-MSH), an endogenous anti-inflammatory peptide known to abrogate ischemia/reperfusion injury. The salutary effects of alpha-MSH in diverse forms of inflammation, combined with its ability to influence multiple pro-inflammatory genes, suggest that it acts at common, early step in the inflammatory cascade, presumably at the level of gene transcription. Accordingly, Aim 4 seeks to characterize mechanism by which alpha-MSH inhibits activation of the molecular stress response controlling the expression of pro-inflammatory genes in cultured macrophage cell lines and intestinal macrophages. These studies involve collaborations with all projects of the Center, and they should provide important insights into the mechanisms by which inflammatory signals alter gene expression in the gut and, more broadly, the pathobiology of MOF. It is anticipated that these studies will facilitate the rational development of novel therapies that selectively and beneficially regulate the expression of genes promoting this syndrome.

肠道灌注不足是创伤患者常见的早期事件，可能进展为多器官衰竭（MOF）。这种缺血/再灌注损伤沉淀了可能促进早期和晚期MOF演变的局部炎症反应。虽然对肠道对休克和缺血/再灌注损伤的病理生理反应了解很多，但对这些损伤在肠道和远端器官中诱导的分子程序或调节这些反应以获得治疗益处的机制知之甚少。该项目旨在通过检查内毒素血症和肠系膜缺血/再灌注损伤动物模型以及培养的小肠上皮细胞和肌层巨噬细胞中肠道、肺和肝脏的应激反应来表征这些信号事件。这些动物和体外数据表征了脂多糖（LPS）给药和肠系膜缺血/再灌注后大鼠肠道、肺和肝脏的分子应激反应。将分析应激激酶级联、诱导型转录因子及其靶促炎基因的激活和细胞分布。在组织水平鉴定的分子信号传导事件将在目标2中使用暴露于LPS或氧化剂应激的小肠上皮细胞和肠道巨噬细胞的培养物进行机械解剖。目的3将检查α-黑素细胞刺激激素（α-MSH）的作用，α-MSH是一种内源性抗炎肽，已知可消除缺血/再灌注损伤。α-MSH在不同形式的炎症中的有益作用，结合其影响多种促炎基因的能力，表明它在炎症级联反应的共同早期步骤中起作用，可能是在基因转录水平上。因此，目的4试图表征α-MSH抑制控制培养的巨噬细胞系和肠巨噬细胞中促炎基因表达的分子应激反应的活化的机制。这些研究涉及与该中心所有项目的合作，它们应该为炎症信号改变肠道基因表达的机制以及更广泛的MOF病理生物学提供重要的见解。预计这些研究将促进新疗法的合理发展，选择性和有益地调节促进这种综合征的基因的表达。