Chronic Stress and Visceral Pain: Role of Intestinal Barrier Dysfunction

摘要 慢性应激与人类内脏痛觉增强(内脏痛觉过敏)有关 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，胃肠病最常见的门诊诊断，影响10%-15%的普通患者 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， 虽然下丘脑-垂体-肾上腺轴的改变被普遍认为是一个促成因素。 最近的研究表明，慢性应激与肠道屏障功能受损、增加有关 上皮细胞旁对大分子的通透性和内脏痛觉过敏。目前还不清楚 肠屏障功能受损是慢性应激性内脏病变发生的先决条件 痛觉过敏。慢性应激是否直接或间接改变上皮紧密连接也是未知的。 蛋白表达，从而增加肠道通透性，最终激活伤害性感受 小路。这个R21应用程序检验了一种挑衅性的假设，即慢性应激诱导的损伤在 肠上皮紧密连接蛋白的表达和功能是脏器发育的先决条件 痛觉过敏。特异性肠上皮紧密连接蛋白的下调是由 应激诱导促炎细胞因子(S)增加，导致细胞旁通透性增加，以及 初级传入伤害性感受通路的激活。强劲的初步数据支持了这一观点的正确性 假设。特定目标1将研究肠道上皮细胞增加之间的潜在因果关系 慢性应激时细胞旁通透性和增强的内脏痛觉。我们假设慢性病 应激与肠道屏障功能受损有关，这种功能先于内脏痛觉过敏，并涉及 增加了对带电和未带电大分子的渗透性。《特定目标2》将阐明 慢性应激所致肠屏障功能损害的分子途径 痛觉过敏。我们假设慢性应激会导致特定的促炎细胞因子升高， 包括IL-6，它先于并介导特定的肠上皮紧密连接的下调 蛋白质，增加大分子通透性，从而导致内脏痛觉过敏。我们建议 促炎细胞因子(S)升高和肠(结肠)上皮细胞旁细胞增多 大分子的渗透性是产生内脏痛觉过敏所必需的。我们认为这些数据 由R21生成，将构成极具竞争力的R01应用程序的基础。

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.