Epithelial-derived mediators of neutrophil infiltration in the intestine

肠道中性粒细胞浸润的上皮源性介质

• 批准号: 8715349
• 负责人: Rose Linda Szabady
• 金额: $ 5.89万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-19 至 2016-06-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715349
• 关键词: Abscess; Acute; Affect; Allergic; American; Apical; Automobile Driving; Bacteria; Biology; Cessation of life; Child; Chronic; Clinical; Colitis; Colon; Crohn' s disease; Development; Diarrhea; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Etiology; Evaluation; Event; Evolution; Female; Foundations; G-Protein-Coupled Receptors; Gastroenteritis; Gastrointestinal tract structure; Gene Targeting; Genetic Predisposition to Disease; Goals; Health; Histologic; Home environment; Homeostasis; Human; Immigration; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Investigation; Lead; Lesion; Lipids; Lung Inflammation; Maintenance; Mediating; Mediator of activation protein; Microbe; Modeling; Morbidity - disease rate; Mucous Membrane; Necrosis; Neutrophil Infiltration; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Phase; Physiological; Population; Process; Public Health; Reactive Oxygen Species; Receptor Gene; Recurrence; Regulation; Relapse; Research; Salmonella; Salmonella infections; Salmonella typhimurium; Shigella dysenteriae; Site; Stimulus; Surface; Symptoms; System; Systemic Therapy; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Ulcer; Ulcerative Colitis; design; enteritis; in vitro testing; in vivo; in vivo Model; intestinal epithelium; intestinal homeostasis; killings; knock-down; male; microbial; migration; mortality; mouse model; mucosal site; neutrophil; novel; pathogen; prevent; public health relevance; receptor; response; therapeutic target; therapy development

DESCRIPTION (provided by applicant): The human intestine is home to a continuous balancing act between the host immune response, the large population of resident bacteria, and the thin epithelial layer that separates them. Disruptions in this fine balance lead to intestinal inflammation, a significant cause of morbidity and mortality worldwide. The idiopathic inflammatory bowel diseases (IBD) impose a significant health and monetary burden in the developed world, with roughly 1 in 200 people in the US affected. In the developing world, infection with microbial pathogens leads to about two billion cases of diarrheal disease annually and 1.5 million deaths, primarily among children. Diarrheal pathogens such as Salmonella Typhimurium cause inflammatory diarrhea that mimics several clinical hallmarks of IBD including massive neutrophil infiltration into the intestine. Understanding the shared mechanisms that drive neutrophil infiltration during disease is therefore of critical importance in public health. Hepoxilin A3 (HXA3) is a lipid secreted from the apical surface of Salmonella- infected epithelial cells that has been identified as a crucial and specific mediator of neutrophil transepithelial migration in the intestine. HXA3 also drives neutrophil infiltration during intestial inflammation triggered by a variety of stimuli as well as during lung inflammation. In addition, we have recently identified an activity secreted by uninfected epithelial cells that inhibits HXA3-mediated migration, which we refer to as AMEND. We hypothesize that the balance between AMEND and HXA3 activity in the intestine regulates the homeostatic set point that must be overcome for the induction of intestinal inflammation. In this application we seek to further understand the interaction between HXA3 and neutrophils, and to investigate the mechanisms by which AMEND regulates HXA3 activity during homeostasis and disease. We will integrate findings in vitro and in vivo to define precise mechanisms of HXA3 and AMEND function during Salmonella infection, and will broaden the applicability of these findings by investigating the regulation of HXA3 activity by AMEND in DSS colitis and T cell transfer, two established mouse models of non-infectious colitis. Identification of the HXA3 receptor will provide a major conceptual advance in the field and identify a potential therapeutic target in inflammatory disease. Similarly, identifying the mechanism(s) by which AMEND regulates HXA3-mediated inflammation will highlight pathways to target for therapeutic intervention. Current therapies for IBD suffer from damaging sequelae and an inability to prevent relapses, with surgical intervention eventually required in 35-40% of ulcerative colitis patients and 70-80% of Crohn's disease patients. Targeting local inflammatory responses rather than systemic therapies may help to reduce damaging sequelae, and directing therapies to block the early steps in initiation of inflammation may have better outcomes in preventing relapse. Furthermore, the studies proposed here will contribute greatly to understanding the basic biology of the epithelium and its ability to control neutrophil recruitment, opening up further research avenues in intestinal biology.

描述（由申请人提供）：人体肠道是宿主免疫反应、大量常驻细菌和分隔它们的薄上皮层之间持续平衡的家园。这种精细平衡的破坏导致肠道炎症，这是世界范围内发病率和死亡率的重要原因。特发性炎症性肠病（IBD）在发达国家造成了重大的健康和经济负担，在美国大约每200人中就有1人受到影响。在发展中国家，微生物病原体感染每年导致约20亿例疟疾病例和150万例死亡，主要是儿童。鼠伤寒沙门氏菌等腹泻病原体会引起炎症性腹泻，类似于IBD的几个临床特征，包括大量中性粒细胞浸润到肠道中。因此，了解疾病过程中驱动中性粒细胞浸润的共同机制对于预防和治疗疾病至关重要。 公共卫生肝氧素A3（HXA 3）是由沙门氏菌感染的上皮细胞顶端表面分泌的脂质，已被鉴定为中性粒细胞的关键和特异性介质 在肠中的跨上皮迁移。HXA 3还在由多种刺激触发的肠道炎症期间以及在肺部炎症期间驱动嗜中性粒细胞浸润。另外我们 最近鉴定了由未感染的上皮细胞分泌的抑制HXA 3介导的迁移的活性，我们将其称为AMEND。我们推测，肠道中AMEND和HXA 3活性之间的平衡调节了稳态设定点，该稳态设定点必须被克服以诱导肠道炎症。在本申请中，我们寻求进一步了解HXA 3和中性粒细胞之间的相互作用，并研究AMEND在稳态和疾病期间调节HXA 3活性的机制。我们将整合体外和体内的研究结果，以确定沙门氏菌感染期间HXA 3和AMEND功能的精确机制，并通过研究DSS结肠炎和T细胞转移（两种已建立的非感染性结肠炎小鼠模型）中AMEND对HXA 3活性的调节来扩大这些研究结果的适用性。HXA 3受体的鉴定将在该领域提供一个重大的概念性进展，并确定一个潜在的治疗靶点在炎症性疾病。类似地，确定AMEND调节HXA 3介导的炎症的机制将突出治疗干预的靶向途径。目前IBD的治疗存在损伤性后遗症，并且无法预防复发，最终35-40%的溃疡性结肠炎患者和70-80%的克罗恩病患者需要手术干预。靶向局部炎症反应而不是全身治疗可能有助于减少损伤性后遗症，并且指导治疗以阻断炎症起始的早期步骤可能在预防复发方面具有更好的结果。此外，本文提出的研究将大大有助于了解上皮细胞的基本生物学及其控制中性粒细胞募集的能力，开辟肠道生物学的进一步研究途径。