Gastric Injury In Trauma and Surgical Sepsis

外伤和手术脓毒症中的胃损伤

• 批准号: 7451320
• 负责人: DAVID I SOYBEL
• 金额: $ 2.56万
• 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/7451320
• 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; 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

The long term goal of thisproject is to understand, at the cellular level, the mechanisms bywhich gastric mucosa protects itself against damage by trauma and systemic sepsis or stress. This proposalfocuses 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 ofZn ([Zn2*]^ 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+]t 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+Ji would be viewed as a protective and anti-apoptotic. However, we also hypothesize that uncontrolled accumulation of[Zn2+]i maycontribute to non-apoptotic, oxidant- induced epithelial cell injury and necrosis. TheSpecific Aims of thisproposal are: 1) to identify alterations in the mechanisms of uptake, release and disposal of labile Z¿2+ 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+J 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. Theproposed studies promise novel insights into the role of Zn2* as an intracellular signal that regulates epithelialfunction 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 bysystemic stress and acute inflammation.

这项运动的长期目标是在细胞水平上了解胃粘膜的机制 保护自己免受创伤和全身性败血症或压力的伤害。此提案在锌上作为信号 胃粘膜中发生的氧化应激，响应损伤，然后是急性炎症。我们的 初步研究表明，细胞内浓度的Zn（[Zn2*] 各种锌转运蛋白，囊泡存储位点和金属结合蛋白的作用低水平 细胞质，其中金属氨酸（MT）是主要储层。我们的研究还表明，暴露于某些 氧化剂导致分泌酸性胃腺的上皮细胞中的[Zn2+] I大幅增加，并且 粘液/HCO3分泌表面上皮。对调节Zn2*稳态的机制知之甚少 通常，通常在胃肠道中的上皮细胞。我们假设这种低氧 损伤和确保炎症反应导致Zn2+的积累 表面上皮。 [Zn2+] t增加的下游后果包括：抑制酸分泌 以及粘膜保护功能的增强，第二诚通路的改变（CA2+，CAMP/PKA，， PKC），糖酵解和线粒体呼吸的约束，以及固有途径的遏制 凋亡。通常，氧化剂引起的[Zn2+JI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会归因于非凋亡，氧化剂 - 诱导上皮细胞损伤和坏死。该权力的三个目标是：1）确定变化 使用体外，摄取，释放和处置不稳定的胃腺和表面上皮的机制 氧化应激模型；评估Zn2+作为氧化应激的细胞内信使，并使用体外和 胃腺和表面上皮功能的体内模型，以监测信号转导中的响应和 响应氧化剂诱导的细胞内改变的凋亡途径[Zn2+J信号； 3）探索 Zn2*作为氧化应激的细胞外信使，使用体外和体内模型 表征胃粘膜的管腔和上皮下空间中的氧化物诱导的灾难 及其对粘膜功能和完整性的影响。这项研究的研究有望对自己的作用进行新颖的见解 Zn2*作为调节胃粘膜上皮功能的细胞内信号。另外，这些研究 可以鉴定通过控制氧化应激期间Zn2+稳态有效的治疗靶标。 这种理论策略不仅适用于胃中的伤害，而且适用于GI的其他地区 区域影响了系统性压力和急性炎症。