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: 8528270
• 负责人: Rose Linda Szabady
• 金额: $ 5.8万
• 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/8528270
• 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; 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; inflammatory disease of the intestine; 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、大量常驻细菌和将它们分开的薄上皮层之间持续平衡的家园。这种微妙平衡的破坏会导致肠道炎症，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）在发达国家造成了严重的健康和经济负担，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20亿腹泻病例和150万人死亡，其中主要是儿童。腹泻病原体如鼠伤寒沙门氏菌引起炎症性腹泻，这种腹泻模仿IBD的几个临床特征，包括大量中性粒细胞浸润到肠道。因此，了解疾病期间驱动中性粒细胞浸润的共同机制对预防疾病至关重要