IL-33 AND EXCESS MUCUS PRODUCTION

IL-33 和粘液分泌过多

基本信息

批准号：
8632665
负责人：
Michael J Holtzman
金额：
$ 48.19万
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/8632665
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 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 public health relevance 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（由申请人提供）：主要的人类气道疾病的特征是气道粘液和感染过多，因此需要新的气道粘液形成假设及其与感染的关系才能理解和治疗这种疾病。该计划集中于IL-33的上皮细胞产生，是气道疾病中过量粘液产生的关键调节剂。该重点来自于由于病毒感染而导致的粘液产生过多的小鼠模型以及由于COPD引起的粘液过量产生过多的人类的转化研究。在小鼠模型中，parainfluenza病毒（PIV）感染导致IL-33的产生，进而导致IL-13先天免疫细胞的产生，并导致气道粘液的过量生产，并通过吸烟增强了此过程。 IL-33的产生可追溯到可能与细胞更新，修复和重塑有关的上皮细胞的亚群。在患有COPD的人类中，IL-33的产量也随着IL-13和气道粘液产生的上调而增加。在这种情况下，IL-33产生的增加可追溯到基底祖细胞的亚群，这些细胞维持内源性能力增加了多能性增加和ATP依赖性IL-33甚至是离体的释放。因此，我们建议可以通过上皮危险信号（尤其是ATP）激活可持续的（祖细胞）上皮细胞种群（尤其是人类的基础lie细胞），从而释放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获得过多的粘液产生的易感性。因此，这些发现可能提供了一种新的范式来解释烟草吸烟和病毒感染在慢性气道疾病过量产生中的作用。我们的初步研究导致了以下特定目的：1。在鼠标模型中：定义IL-33的功能细胞源和目标，这些功能细胞源和目标是在病毒后小鼠模型中过量的气道粘液产生的基础，并在体内吸烟或没有烟草吸烟，并建立IL-33产生/释放/复发细胞的存在，并使用这种模型进行了这种模型，并使用这种模型进行了对应量和对应量。 2。在人类中：建立与IL-33表达/释放的祖细胞群相关的祖细胞群，与基线时COPD的粘液过量产生相关，在病毒诱导的体内加重（使用临床样品）和体外（使用与这些样品中隔离的上皮细胞）中的病毒诱导的加重。这些研究将测试我们对IL-33表达的建议，并从特定的上皮祖细胞中释放，该祖先群体表现出增加的自我更新能力，IL-33释放和粘液细胞分化和从而导致了一个恶性循环，其中吸烟和感染会导致慢性过量的粘液产生。