IL-33 AND EXCESS MUCUS PRODUCTION

IL-33 和粘液分泌过多

基本信息

批准号：
8996714
负责人：
Michael J Holtzman
金额：
$ 47.06万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-10 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996714
关键词：
Address Bone Marrow Cause of Death Cell Differentiation process Cells Chimera organism Chronic Chronic Obstructive Airway Disease Clinical Development Disease Elements Epithelial Epithelial Cells Exhibits Health Human Immune In Vitro Infection Influenza A virus Interleukin-13 Knockout Mice Lead Link Lung Lung Transplantation Lung diseases Modeling Morbidity - disease rate Mucous body substance Mus Myelogenous Nature Parainfluenza Virus Infections Pathway interactions Patients Population Predisposition Process Production Protocols documentation Public Health Reporter Role Sampling Sendai virus Signal Transduction Site Smoke Smoking Source Stem cells Stromal Cells System Testing Tobacco smoking Tracheobronchial Up-Regulation Viral Virus Virus Diseases airway obstruction base cell type design effective therapy in vivo mortality mouse model parainfluenza virus pluripotency progenitor repaired research study self-renewal translational study

项目摘要

DESCRIPTION (provided by applicant): Major human airway diseases are characterized by excessive airway mucus and infection so that new hypotheses for airway mucus formation and its relationship to infection are required to understand and treat this type of disease. This projet concentrates on epithelial cell production of IL-33 as a critical regulator of excess mucus production in airway disease. The focus derives from findings in both a mouse model of excess mucus production due to viral infection and in translational studies of humans with excess mucus production due to COPD. In the mouse model, parainfluenza virus (PIV) infection leads to production of IL-33 and in turn innate immune cell production of IL-13 and consequent overproduction of airway mucus, and this process is enhanced by tobacco smoking. IL-33 production is traceable to a subpopulation of epithelial cells that may be linked to cell renewal, repair, and remodeling. In humans with COPD, IL-33 production is also increased in concert with up-regulation of IL-13 and airway mucus production. In this case, increased IL-33 production is traceable to a subpopulation of basal progenitor cells that maintain an endogenous capacity for increased pluripotency and ATP-dependent release of IL-33 even ex vivo. We therefore propose that a sustainable (progenitor) epithelial cell population (particularly basal-lie cells in humans) may be activated by epithelial danger signals (particularly ATP) to release IL-33 and thereby lead to excess airway mucus production. The progenitor nature of this IL-33-expressing ATP-responsive cell population could explain an acquired susceptibility to excess mucus production. The findings may therefore provide a new paradigm to explain the role of tobacco smoking and viral infection in the excess mucus production of chronic airway disease. Our preliminary studies lead to the following specific aims: 1. In mouse models: Define the functional cell sources and targets of IL-33 that underlie excess airway mucus production in a postviral mouse model with or without tobacco smoking in vivo and establish the existence of an IL-33-producing/releasing epithelial progenitor cell population using this model and the corresponding mouse cells studied in vitro. 2. In humans: Establish the existence of an IL-33-expressing/releasing progenitor cell population linked to excess mucus production in patients with COPD at baseline and during virus-induced exacerbation in vivo (using clinical samples) and in vitro (using epithelial cells isolated from these samples). These studies will test our proposal for IL-33 expression and release from a specific epithelial progenitor population that exhibits increased capacities for self-renewal, IL-33 release, and mucous cell differentiation, and thereby contributes to a vicious cycle wherein smoking and infection lead to chronic excess mucus production.

描述（申请人提供）：人类主要气道疾病的特征是气道粘液过多和感染，因此需要对气道粘液形成及其与感染的关系提出新的假设来理解和治疗此类疾病。该项目专注于上皮细胞产生 IL-33，作为气道疾病中粘液过多产生的关键调节因子。焦点源自病毒感染导致粘液分泌过多的小鼠模型以及慢性阻塞性肺病导致粘液分泌过多的人类转化研究的发现。在小鼠模型中，副流感病毒 (PIV) 感染导致产生 IL-33，进而导致先天免疫细胞产生 IL-13，进而导致气道粘液过量产生，而吸烟会增强这一过程。 IL-33 的产生可追溯到上皮细胞亚群，该亚群可能与细胞更新、修复和重塑有关。在患有慢性阻塞性肺病的人类中，IL-33 的产生也随着 IL-13 和气道粘液产生的上调而增加。在这种情况下，IL-33 产量的增加可追溯到基底祖细胞的亚群，该亚群即使在体外也维持增加多能性和 ATP 依赖性 IL-33 释放的内源能力。因此，我们提出，可持续的（祖细胞）上皮细胞群（特别是人类的基底细胞）可能会被上皮危险信号（特别是 ATP）激活，释放 IL-33，从而导致气道粘液产生过多。这种表达 IL-33 的 ATP 响应细胞群的祖细胞性质可以解释对过量粘液产生的获得性敏感性。因此，这些发现可能提供一个新的范例来解释吸烟和病毒感染在慢性气道疾病粘液分泌过多中的作用。我们的初步研究实现了以下具体目标： 1. 在小鼠模型中：在体内吸烟或不吸烟的病毒后小鼠模型中，确定 IL-33 的功能细胞来源和靶点，这些细胞来源和靶点是导致呼吸道粘液过量产生的原因，并确定是否存在使用该模型和体外研究的相应小鼠细胞构建了产生/释放 IL-33 的上皮祖细胞群。 2. 在人类中：在体内（使用临床样本）和体外（使用上皮细胞样本）确定 COPD 患者基线和病毒诱导恶化期间是否存在表达/释放 IL-33 的祖细胞群，该祖细胞群与 COPD 患者的过量粘液产生有关。从这些样品中分离出的细胞）。这些研究将测试我们关于特定上皮祖细胞群中 IL-33 表达和释放的建议，该细胞群表现出自我更新、IL-33 释放和粘液细胞分化能力增强，以及从而导致恶性循环，其中吸烟和感染导致慢性粘液分泌过多。