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 在刺激性肠综合征（ISS）的亚竞选中自由观察到内脏超敏反应 患者尚不清楚临床研究 显示粘膜炎症的亚临床迹象，伴随着肠道渗透性的增加。 因此可以想象，粘膜屏障毛茸茸的furrier FuncritatedE增加了抗原 呈粘膜中的免疫细胞，导致违反。 通过产生造影剂和痛苦，在先天免疫免疫防御中发挥重要作用 可能引起内脏的过敏性的介体。 源自omega-3多不饱和脂肪的内源性抗炎脂质介质的一类 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 功能和调节感觉阈值。 与肠道营养不良的患者相比 在健康对照中观察到的 内脏的超敏反应。 在结肠组织中的分辨率和内脏机械灵敏度之间； 检查分辨率抑制粘膜发炎并减少内脏的机制 高敏性。我们假设结肠组织中的RVD1水平 机械灵敏度。 促炎介质的合成，并降低感觉神经元的兴奋性，以防止 内脏性超敏反应的发展。 甲基肽受体2（FPR2）/GαI的作用减少cAMP的形成。 我们有3个特定目标：目标1：使用2个啮齿动物模型，其中结肠RVD1水平是模块化的 饮食因素和肠道微生物群，我们旨在证明您的RVD1水平 结肠组织在调节内脏机械灵敏度中起重要作用； RVD1的体外抑制肥大细胞和 和内脏的超敏反应的发展。 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。 新型治疗剂可减少粘膜下炎症并减轻IBS患者的疼痛。