Actions of Resolvins on Intestinal Inflammation and Pain

Resolvins 对肠道炎症和疼痛的作用

• 批准号: 10597042
• 负责人: JOHN W WILEY
• 金额: $ 46.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597042
• 关键词: Abdominal Pain; Acids; Afferent Neurons; Analgesics; Anti-Inflammatory Agents; Antigen Presentation; Biopsy; Biopsy Specimen; Cell Degranulation; Cell Extracts; Cell Line; Cell physiology; Cells; Clinical Research; Colon; Cyclic AMP; Data; Development; Diet; Dietary Factors; Dinoprostone; Docosahexaenoic Acids; Electrophysiology (science); Exhibits; Exposure to; FPR2 gene; Fish Oils; Germ-Free; Histamine; Human; Hypersensitivity; Immune; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Intestinal permeability; Intracolonic; Irritable Bowel Syndrome; LOX gene; Mechanical Stimulation; Mechanics; Mediating; Mediator; Modeling; Mucositis; Mucous Membrane; Mus; Neurons; Omega-3 Fatty Acids; Pain; Pathway interactions; Patients; Play; Property; Resistance; Rodent; Rodent Model; Role; Sensory Thresholds; Signal Transduction Pathway; Submucosa; TNF gene; TRPV1 gene; Testing; Therapeutic Agents; Tissues; Visceral; antagonist; cytokine; effective therapy; experience; gut dysbiosis; gut homeostasis; gut inflammation; gut microbiota; immune function; immunoregulation; in vivo; indium arsenide; inhibitor; lipid mediator; mast cell; novel; novel therapeutics; patch clamp; prevent; receptor; reconstitution

PROJECT ABSTRACT Visceral hypersensitivity is frequently observed in a subpopulation of irritable bowel syndrome (IBS) patients. The responsible mechanism is unclear. Clinical studies show that many of these patients display subclinical signs of mucosal inflammation accompanied by increased gut permeability. It is therefore conceivable that impaired mucosal barrier function may facilitate increased antigen presentation to the immune cells in the submucosa, resulting in inflammation. Mast cells been shown to play important roles in the innate immune defense by producing proinflammatory agents and pain mediators which may induce visceral hypersensitivity. Our preliminary data show that resolvins, a novel class of endogenous anti-inflammatory lipid mediators derived from omega-3 polyunsaturated fatty acids, are present in the colonic mucosa and play an important role in regulating submucosal mast cell function and modulating the sensory threshold. Furthermore, our clinical studies show that in IBS-D patients with gut dysbiosis, the level of colonic resolvin D1 (RvD1) is significantly reduced compared to that observed in healthy controls. We also observed that resolvin-deficient mice exhibit evidence of visceral hypersensitivity. The objectives of our studies are 1. to investigate the functional relationship between the level of resolvins in the colonic tissue and visceral mechanical sensitivity; and 2. to examine the mechanisms by which resolvins inhibit mucosal inflammation and reduce visceral hypersensitivity. We hypothesize that the level of RvD1 in the colonic tissue modulates visceral mechanical sensitivity. We further propose that RvD1 mechanistically controls mast cell activation and synthesis of proinflammatory mediators, and decreases the excitability of sensory neurons, preventing the development of visceral hypersensitivity. These beneficial actions of RvD1 are mediated through the action of formyl peptide receptor 2 (FPR2)/ Gαi to reduce cAMP formation. To test this hypothesis, we have 3 specific aims: Aim 1: Using 2 rodent models in which colonic RvD1 levels are modulated by dietary factors and gut microbiota, respectively, we aim to demonstrate that the levels of RvD1 in the colonic tissue play an important role in regulating visceral mechanical sensitivity; Aim 2: To show in vivo and in vitro that RvD1 inhibits the degranulation of mast cells and prevents submucosal inflammation and the development of visceral hypersensitivity. Aim 3: To demonstrate that RVD1 modulates the excitability of gut-protecting DRG neurons by activating the FPR2 receptor, which in turn reduces intracellular cAMP levels. Results from these studies will support the use of resolvins as a class of novel therapeutic agents to reduce submucosal inflammation and decrease pain in IBS patients.

项目摘要 在肠易激综合征（IBS）的亚群中经常观察到内脏超敏反应 患者。负责任的机制尚不清楚。临床研究表明，其中许多患者 显示通过肠道渗透性增加完成的粘膜注射的亚临床迹象。这是 因此可以想象，粘膜屏障功能受损可能会促进抗原增加 向粘膜下的免疫细胞呈现，导致炎症。肥大细胞显示为 通过产生促炎剂和痛苦，在先天免疫防御中发挥重要作用 可能引起内脏超敏反应的介体。我们的初步数据表明，Resolvins是一种小说 源自omega-3多不饱和脂肪的内源性抗炎脂质介质 酸存在于结肠粘膜中，并在调节粘膜下肥料细胞中起重要作用 功能并调节感觉阈值。此外，我们的临床研究表明，在IBS-D中 与肠道营养不良的患者相比 在健康对照中观察到的。我们还观察到，分离缺陷小鼠表现出 内脏超敏反应。我们研究的目标是1。 在结肠组织中的分解水平和内脏的机械灵敏度之间；和2 检查分辨抑制粘膜注射并减少内脏的机制 高敏性。我们假设结肠组织中的RVD1水平调节内脏 机械灵敏度。我们进一步建议RVD1机械控制肥大细胞的激活和 促炎性介体的合成，并减少感觉神经元的兴奋，以防止 内脏超敏反应的发展。 RVD1的这些有益动作是通过 配方肽受体2（FPR2）/GαI减少cAMP形成的作用。为了检验这一假设， 我们有3个具体目标：目标1：使用2个啮齿动物模型，其中结肠RVD1水平由 饮食因素和肠道微生物群，我们旨在证明RVD1水平 结肠组织在调节内脏机械敏感性方面起重要作用。目标2：显示体内 RVD1的体外抑制肥大细胞的脱粒并防止粘膜下注射 以及内脏超敏反应的发展。目标3：证明RVD1调节 通过激活FPR2受体来保护肠道的DRG神经元的兴奋性，进而减少 细胞内营地水平。这些研究的结果将支持使用ResolveVins作为一类 新型的热剂可减少粘膜下感染并减轻IBS患者的疼痛。