Chronic Stress and Visceral Pain: Role of Intestinal Barrier Dysfunction

慢性压力和内脏疼痛：肠屏障功能障碍的作用

• 批准号: 9167138
• 负责人: SHUANGSONG HONG
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167138
• 关键词: Abdominal Pain; Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biological Assay; Charge; Chronic; Chronic stress; Clinic; Clinical; Colon; Complex; Corticosterone; Data; Development; Diagnosis; Distal; Down-Regulation; Epithelial; Foundations; Functional disorder; Gastroenterology; Gene Silencing; General Population; Glucocorticoid Receptor; Harvest; Human; Human Cell Line; Hydrocortisone; Hyperalgesia; Impairment; In Situ; In Vitro; Inflammatory; Interleukin-6; Intestines; Investigation; Irritable Bowel Syndrome; Longitudinal Studies; Measures; Mediating; Modeling; Molecular; Mucous Membrane; Nociception; Outpatients; Pain; Pathogenesis; Pathway interactions; Patients; Perception; Permeability; Pharmaceutical Preparations; Production; Proteins; Rattus; Role; Spinal; Spinal Ganglia; Stress; Tight Junctions; Time; Tissues; Visceral; Visceral pain; Water; abstracting; base; central sensitization; cytokine; glucocorticoid-induced orphan receptor; hypothalamic-pituitary-adrenal axis; in vivo; macromolecule; prevent; protein expression; protein function; response

Abstract Chronic stress is associated with enhanced visceral pain perception (visceral hyperalgesia) in the human and animal models. An example of chronic stress-associated visceral hyperalgesia in the clinic is Irritable Bowel Syndrome, the most common outpatient diagnosis in Gastroenterology, affecting 10-15% of the general population. The pathways, cellular and molecular mechanisms underlying chronic stress-induced visceral pain are an active area of investigation without a potentially unifying mechanism to explain the pathogenesis, although alterations in the Hypothalamic-Pituitary-Adrenal axis are generally accepted as a contributing factor. Recent studies suggest that chronic stress is associated with impaired intestinal barrier function, increased epithelial paracellular permeability to macromolecules and visceral hyperalgesia. It is unknown whether impaired intestinal barrier function is a prerequisite for the development of chronic stress-induced visceral hyperalgesia. It is also unknown whether chronic stress directly or indirectly alters epithelial tight junction protein expression and, thereby, increases intestinal permeability culminating in activation of nociceptive pathways. This R21 application examine the provocative hypothesis that chronic stress-induced impairment in intestinal epithelial tight junction protein expression and function is a prerequisite for development of visceral hyperalgesia. Down-regulation involving specific intestinal epithelial tight junction proteins is mediated by stress-induced increase in pro-inflammatory cytokine(s) resulting in increased paracellular permeability, and activation of primary afferent nociceptive pathways. Strong preliminary data supports the validity of this hypothesis. Specific Aim 1 will examine a potential causal role between increases in intestinal epithelial paracellular permeability and enhanced visceral pain perception in chronic stress. We hypothesize that chronic stress is associated with impaired intestinal barrier function that precedes visceral hyperalgesia and involves increased permeability to both charged and uncharged macromolecules. Specific Aim 2 will elucidate the molecular pathway that underlies chronic stress-mediated impairment in intestinal barrier function and hyperalgesia. We hypothesize that chronic stress causes elevation in specific pro-inflammatory cytokines, including IL-6, which precedes and mediates down-regulation of specific intestinal epithelial tight junction proteins, increase in macromolecular permeability and consequently visceral hyperalgesia. We propose that both elevation of pro-inflammatory cytokine(s) and increased intestinal (colon) epithelial paracellular permeability to macromolecules are required to produce visceral hyperalgesia. We believe that the data generated with the R21 will form the foundation of a highly competitive R01 application.

摘要 慢性应激与人类内脏疼痛感知增强（内脏痛觉过敏）相关， 动物模型临床上慢性应激相关内脏痛觉过敏的一个例子是肠易激综合征 综合征是胃肠病学最常见的门诊诊断，影响10 - 15%的一般 人口慢性应激性内脏痛的通路、细胞和分子机制 是一个活跃的研究领域，没有潜在的统一机制来解释发病机制， 尽管下丘脑-垂体-肾上腺轴的改变通常被认为是一个影响因素。 最近的研究表明，慢性应激与肠道屏障功能受损，增加 上皮细胞对大分子的旁通透性和内脏痛觉过敏。尚不清楚是否 肠屏障功能受损是慢性应激性内脏损害发生的先决条件。 痛觉过敏慢性应激是否直接或间接改变上皮紧密连接也不清楚 蛋白质表达，从而增加肠通透性，最终激活伤害感受性神经元。 途径。这个R21应用程序检查了一个挑衅性的假设，即慢性应激诱导的损伤， 肠上皮紧密连接蛋白表达和功能是内脏器官发育的先决条件 痛觉过敏涉及特定肠上皮紧密连接蛋白的下调是由 应激诱导促炎细胞因子增加，导致细胞旁通透性增加，和 初级传入伤害感受通路的激活。强有力的初步数据支持这一有效性 假说.具体目标1将检查肠上皮细胞增加之间的潜在因果关系， 细胞旁通透性和增强的内脏疼痛感知慢性应激。我们假设慢性的 应激与内脏痛觉过敏之前的肠屏障功能受损有关， 增加了对带电和不带电大分子的渗透性。具体目标2将阐明 作为慢性应激介导的肠屏障功能损害的基础的分子途径， 痛觉过敏我们假设慢性压力会导致特定的促炎细胞因子升高， 包括IL-6，其先于并介导特异性肠上皮紧密连接的下调 蛋白质，大分子渗透性增加，从而内脏痛觉过敏。我们建议 促炎细胞因子升高和肠（结肠）上皮细胞旁 大分子的渗透性是产生内脏痛觉过敏所必需的。我们相信这些数据 R21所产生的能量将构成极具竞争力的R01应用的基础。