Epithelial-derived mediators of neutrophil infiltration in the intestine

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场所。这种微妙平衡的破坏会导致肠道炎症，这是全球发病率和死亡率的一个重要原因。特发性炎症性肠病(IBD)在发达国家造成了巨大的健康和金钱负担，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，会引起炎症性腹泻，这与IBD的几个临床特征相似，包括大量中性粒细胞渗入肠道。因此，了解在疾病过程中驱动中性粒细胞渗透的共同机制在 公共卫生。海波西林A3(HXA3)是一种从沙门氏菌感染的上皮细胞顶面分泌的脂质，已被确认为中性粒细胞的重要和特异的介质 肠道内的跨上皮迁移。HXA3还在各种刺激引发的肠道炎症和肺部炎症过程中促进中性粒细胞的渗透。此外，我们 最近发现了一种由未感染的上皮细胞分泌的抑制HXA3介导的迁移的活性，我们称之为修正。我们假设，肠道中的ADMAND和HXA3活性之间的平衡调节了必须克服的稳态设定点，以诱导肠道炎症。在这一应用中，我们试图进一步了解HXA3和中性粒细胞之间的相互作用，并探讨在体内平衡和疾病期间，ADM调节HXA3活性的机制。我们将结合体外和体内的研究结果来确定HXA3在沙门氏菌感染过程中的确切机制和修正功能，并将通过研究在DSS结肠炎和T细胞转移这两种已建立的非感染性结肠炎小鼠模型中对HXA3活性的调节来扩大这些发现的适用性。HXA3受体的鉴定将在该领域提供重大的概念性进展，并确定炎症性疾病的潜在治疗靶点。同样，找出ADM调节HXA3介导的炎症的机制(S)将突出靶向治疗干预的途径。目前IBD的治疗方法存在破坏性后遗症和无法防止复发的问题，35-40%的溃疡性结肠炎患者和70%-80%的克罗恩病患者最终需要手术治疗。针对局部炎症反应而不是全身治疗可能有助于减少破坏性后遗症，指导治疗以阻止炎症启动的早期步骤可能在防止复发方面有更好的结果。此外，本文提出的研究将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，为肠道生物学开辟进一步的研究途径。

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.