Gastric Injury In Trauma and Surgical Sepsis

外伤和手术脓毒症中的胃损伤

• 批准号: 7277828
• 负责人: DAVID I SOYBEL
• 金额: $ 24.29万
• 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/7277828
• 关键词: Acids; Acute; Affect; Apoptosis; Apoptotic; Binding Proteins; Cells; Containment; Cyclic AMP; Cytoplasm; Epithelial; Epithelial Cells; Epithelium; Exposure to; Gastric Glands; Gastric mucosa; Gastrointestinal tract structure; Gland; Glycolysis; Goals; Homeostasis; Hypoxia; In Vitro; Inflammation; Inflammatory Response; Injury; Lead; Metallothionein; Metals; Mitochondria; Monitor; Mucous body substance; Necrosis; None or Not Applicable; Operative Surgical Procedures; Oxidants; Oxidative Stress; Pathway interactions; Respiration; Role; Second Messenger Systems; Sepsis; Signal Transduction; Site; Stomach; Stress; Surface; Therapeutic; Trauma; Zinc; acute stress; cell injury; in vitro Model; in vivo Model; insight; novel; response; response to injury; restraint; second messenger; therapeutic target; uptake; zinc-binding protein

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）： 本项目的长期目标是在细胞水平上了解胃粘膜保护自身免受创伤和全身性脓毒症或应激损伤的机制。该建议的重点是锌作为氧化应激的信号，发生在胃粘膜中，以响应急性炎症后的损伤。我们的初步研究表明，细胞内的Zn（[Zn 2 +]i）浓度维持在非常低的水平的各种锌转运蛋白，囊泡存储网站，和金属结合蛋白在细胞质中，其中金属硫蛋白（MT）是一个主要的水库的行动。我们的研究还表明，暴露于某些氧化剂导致[Zn 2 +]i在胃酸分泌的胃腺和粘液/HCO 3分泌的表面上皮细胞的显着增加。很少有人知道的机制，调节锌+稳态上皮细胞的胃粘膜-或在胃肠道一般。我们推测，缺氧损伤和随后的炎症反应导致积累的Zn 2+，在细胞的腺体和表面上皮。[Zn 2 +]i增加的下游后果包括：抑制酸分泌和增强粘膜保护功能，改变第二信使途径（Ca 2+，cAMP/PKA，PKC），抑制糖酵解和线粒体呼吸，以及抑制细胞凋亡的内在途径。一般来说，氧化剂诱导的[Zn 2 +]i增加将被视为保护性和抗凋亡。然而，我们还假设，[Zn 2 +]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。本研究的具体目的是：1）利用体外氧化应激模型，鉴定不稳定的胃腺体和表面上皮细胞对Zn ~（2+）的摄取、释放和处置机制的改变;为了评价Zn 2+作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细胞凋亡途径中的反应，对氧化剂诱导的细胞内[Zn 2 +]信号改变的反应; 3）探索Zn 2+作为氧化应激的细胞外信使的作用，使用体外和体内模型来表征氧化剂诱导的胃粘膜腔和上皮下空间中[Zn 2 +]的紊乱及其对粘膜功能和完整性的影响。拟议的研究承诺新的见解的作用，锌2+作为一种细胞内信号，调节上皮细胞功能的胃粘膜。此外，这些研究可能会确定通过控制氧化应激期间Zn 2+稳态而有效的治疗靶点。这种治疗策略不仅适用于胃损伤，而且适用于受全身应激和急性炎症影响的胃肠道其他区域。