Actions of Resolvins on Intestinal Inflammation and Pain

Resolvins 对肠道炎症和疼痛的作用

• 批准号: 10370415
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370415
• 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 Bowel Diseases; Intestinal permeability; Intracolonic; Irritable Bowel Syndrome; LOX gene; Mechanical Stimulation; Mechanics; Mediating; Mediator of activation protein; 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; base; cytokine; effective therapy; experience; gut dysbiosis; gut homeostasis; gut inflammation; gut microbiota; immune function; 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 内脏超敏反应经常在肠易激综合征（IBS）的亚群中观察到 患者责任机制尚不清楚。临床研究表明，许多患者 显示粘膜炎症的亚临床体征，伴有肠通透性增加。是 因此，可以想象，受损的粘膜屏障功能可以促进抗原增加， 在一些实施方案中，免疫球蛋白被呈递给粘膜下层中的免疫细胞，导致炎症。肥大细胞被证明 通过产生促炎剂和疼痛在先天免疫防御中发挥重要作用 可能诱发内脏高敏感性的介质。我们的初步数据表明，resolvins，一种新的 一类来源于ω-3多不饱和脂肪酸的内源性抗炎脂质介质 酸，存在于结肠粘膜中，并在调节粘膜下肥大细胞中起重要作用 功能和调节感觉阈值。此外，我们的临床研究表明，在IBS-D 在患有肠道生态失调的患者中，结肠消退素D1（RvD 1）的水平与对照组相比显著降低。 在健康对照组中观察到的。我们还观察到消退素缺陷小鼠表现出 内脏高敏感性我们的研究目标是1。研究功能关系 结肠组织中的消退素水平与内脏机械敏感性之间的关系;以及2.到 研究消退素抑制粘膜炎症和减少内脏炎症的机制。 超敏反应我们假设结肠组织中RvD 1的水平调节内脏 机械灵敏度我们进一步提出，RvD 1在机制上控制肥大细胞活化， 促炎介质的合成，并降低感觉神经元的兴奋性，防止 内脏高敏感性的发展。RvD 1的这些有益作用通过以下途径介导： 甲酰肽受体2（FPR 2）/ Gαi减少cAMP形成的作用。为了验证这个假设， 我们有3个具体的目的：目的1：使用2种啮齿动物模型，其中结肠RvD 1水平被 饮食因素和肠道微生物群，我们的目的是证明RvD 1的水平， 结肠组织在内脏机械敏感性的调节中起重要作用;目的2：在体内显示 并且在体外RvD 1抑制肥大细胞的脱粒并防止粘膜下炎症 以及内脏高敏感性的发展。目的3：证明RVD 1调节 通过激活FPR 2受体，保护DRG神经元的肠道兴奋性，从而降低 细胞内cAMP水平。这些研究的结果将支持使用消退素作为一类 用于减轻IBS患者的粘膜下炎症和疼痛的新型治疗剂。