Gastric Injury In Trauma and Surgical Sepsis

外伤和手术脓毒症中的胃损伤

• 批准号: 6972965
• 负责人: DAVID I SOYBEL
• 金额: $ 25.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-09 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972965
• 关键词: apoptosis; biological signal transduction; chemical structure function; dietary supplements; gastric mucosa; glycolysis; immune response; inflammation; laboratory rabbit; oxidative stress; second messengers; septicemia; trauma; zinc

DESCRIPTION (provided by applicant): The long term goal of this project is to understand, at the cellular level, the mechanisms by which gastric mucosa protects itself against damage by trauma and systemic sepsis or stress. This proposal focuses on zinc as a signal of oxidative stress that occurs in gastric mucosa in response to injury followed by acute inflammation. Our preliminary studies suggest that the intracellular concentration of Zn ([Zn2+]i) is maintained at extraordinarily low levels by the actions of various zinc transporters, vesicular storage sites, and metal binding proteins in the cytoplasm, of which metallothionein (MT) is a major reservoir. Our studies also indicate that exposure to some oxidants leads to substantial increases in [Zn2+]i in epithelial cells of the acid-secreting gastric glands and mucus/HCO3-secreting surface epithelium. Little is known of the mechanisms regulating Zn2+ homeostasis in epithelial cells of the gastric mucosa- or in the gastrointestinal tract generally. We hypothesize that hypoxic injury and the ensuing inflammatory response lead to accumulation of Zn2+, in cells of the glands and of the surface epithelium. The downstream consequences of increases in [Zn2+]i include: suppression of acid secretion and enhancement of mucosal protective functions, alterations in second messenger pathways (Ca2+, cAMP/PKA, PKC), restraint of glycolysis and mitochondrial respiration, and containment of the intrinsic pathway of apoptosis. In general, oxidant-induced increases in [Zn2+]i would be viewed as a protective and anti-apoptotic. However, we also hypothesize that uncontrolled accumulation of [Zn2+]i may contribute to non-apoptotic, oxidantinduced epithelial cell injury and necrosis. The Specific Aims of this proposal are: 1) to identify alterations in the mechanisms of uptake, release and disposal of labile Zn2+ gastric glands and surface epithelium, using in vitro models of oxidative stress; to evaluate Zn2+ as an intra-cellular messenger of oxidative stress, using in vitro and in vivo models of gastric gland and surface epithelial function to monitor responses in signal transduction and apoptosis pathways in response to oxidant-induced alterations in intracellular [Zn2+] signals; and 3) to explore the role of Zn2+ as an extra-cellular messenger of oxidative stress, using both in vitro and in vivo models to characterize oxidant-induced disturbances in [Zn2+] in the the lumen and subepithelial spaces of gastric mucosa and their effects on mucosal function and integrity. The proposed studies promise novel insights into the role of Zn2+ as an intracellular signal that regulates epithelial function in the gastric mucosa. In addition, these studies may identify therapeutic targets that are effective through control of Zn2+ homeostasis during oxidative stress. Such therapeutic strategies would be applicable not only to injury in the stomach, but to other regions of the GI tract affected by systemic stress and acute inflammation.

描述（由申请人提供）： 该项目的长期目标是在细胞水平上了解胃粘膜保护自己免受创伤和全身性败血症或压力损害的机制。该提案的重点是锌作为氧化应激的信号，该信号是胃粘膜发生的，响应损伤，然后是急性炎症。我们的初步研究表明，Zn（[Zn2+] i）的细胞内浓度通过各种锌转运蛋白，囊泡储存位点和金属结合蛋白的作用保持在极低的水平，而金属素（MT）的细胞质中的金属结合蛋白是主要的储层。我们的研究还表明，暴露于某些氧化剂会导致分泌酸性胃腺的上皮细胞和粘液/HCO3分泌表面上皮的[Zn2+] I的大幅增加。对于调节胃粘膜上皮细胞中Zn2+稳态的机制几乎不知所知。我们假设低氧损伤和随之而来的炎症反应导致Zn2+在腺体和表面上皮的细胞中积累。 [Zn2+]增加的下游后果包括：抑制酸性分泌和粘膜保护功能的增强，第二信使途径的改变（CA2+，CAMP/PKA，PKA），糖酸溶解的约束和线粒体呼吸的约束以及内在途径的内在途径的包含。通常，氧化剂引起的[Zn2+]的增加将被视为一种保护性和抗凋亡。但是，我们还假设[Zn2+] I的不受控制的积累可能有助于非凋亡，氧化诱导的上皮细胞损伤和坏死。该提案的具体目的是：1）使用氧化应激的体外模型，确定不稳定Zn2+胃腺和表面上皮的摄取，释放和处置机制的改变；将Zn2+评估为氧化应激的细胞内信使，使用胃腺和表面上皮功能的体外和体内模型来监测信号转导和凋亡途径中的反应，以响应氧化剂诱导的细胞内[Zn2+]信号的氧化诱导的变化； 3）探索Zn2+作为氧化应激的细胞外信使的作用，使用体外和体内模型都表征了胃粘膜的腔内和下皮下空间中氧化剂诱导的干扰，及其对粘膜功能和完整性的影响。拟议的研究确保了对Zn2+作为调节胃粘膜上皮功能的细胞内信号的作用的新见解。此外，这些研究可能会确定通过在氧化应激过程中控制Zn2+稳态有效的治疗靶标。这种治疗策略不仅适用于胃部受伤，而且适用于受系统性压力和急性炎症影响的胃肠道的其他区域。