IL-33 AND EXCESS MUCUS PRODUCTION

描述（由申请人提供）：人类重大气道疾病的特征是气道粘液和感染过多，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，以了解和治疗这类疾病。这个项目集中在上皮细胞产生IL-33作为气道疾病中过量粘液产生的关键调节因子。该研究的重点来自病毒感染导致粘液分泌过多的小鼠模型和COPD导致粘液分泌过多的人类转译研究的发现。在小鼠模型中，副流感病毒（PIV）感染导致IL-33的产生，进而导致先天免疫细胞产生IL-13，从而导致气道粘液的过量产生，这一过程因吸烟而增强。IL-33的产生可追溯到上皮细胞亚群，可能与细胞更新、修复和重塑有关。在COPD患者中，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，增加的IL-33产生可追溯到基底祖细胞亚群，这些细胞保持内源性能力，增加多能性和atp依赖性释放IL-33，甚至在体外。因此，我们提出一个可持续的（祖）上皮细胞群（特别是人类的基底细胞）可能被上皮危险信号（特别是ATP）激活，释放IL-33，从而导致气道粘液过量产生。这种表达il -33的atp应答细胞群的祖细胞性质可以解释对过量粘液产生的获得性易感性。因此，这一发现可能为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提供了一种新的范式。我们的初步研究导致以下具体目标：1。在小鼠模型中：确定IL-33的功能细胞来源和靶点，这些细胞是在体内吸烟或不吸烟的病毒后小鼠模型中过量气道粘液产生的基础，并利用该模型和相应的小鼠细胞在体外研究中建立IL-33产生/释放上皮祖细胞群的存在。2. 在人类中：在体内（使用临床样本）和体外（使用从这些样本中分离的上皮细胞）中，确定存在il -33表达/释放祖细胞群，这些祖细胞群与COPD患者在基线和病毒诱导加重期间过量粘液产生有关。这些研究将验证我们提出的IL-33在特定上皮祖细胞群体中表达和释放的建议，该群体表现出自我更新、IL-33释放和粘液细胞分化的能力增强

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.