IL-33 AND EXCESS MUCUS PRODUCTION

描述(申请人提供)：人类主要呼吸道疾病的特点是呼吸道粘液过多和感染，因此需要对呼吸道粘液的形成及其与感染的关系提出新的假说，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，作为呼吸道疾病中过度粘液产生的关键调节因素。这一焦点来自病毒感染所致粘液过量产生的小鼠模型以及COPD所致粘液过度产生的人类翻译研究。在小鼠模型中，副流感病毒(PIV)感染导致IL-33的产生，进而导致天然免疫细胞产生IL-13，从而导致呼吸道粘液的过度产生，而吸烟促进了这一过程。IL-33的产生可以追溯到上皮细胞亚群，这可能与细胞更新、修复和重塑有关。在患有COPD的人类中，IL-33的产生也随着IL-13的上调和呼吸道粘液的产生而增加。在这种情况下，IL-33产量的增加可以追溯到基本祖细胞亚群，这些细胞亚群即使在体外也保持着增强多能性和依赖于ATP的IL-33释放的内源性能力。因此，我们认为一个可持续的(祖细胞)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，从而释放IL-33，从而导致过度的呼吸道粘液产生。这种表达IL-33的ATP反应细胞群体的祖细胞性质可以解释对过度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呼吸道疾病过度粘液产生中的作用提供了一个新的范式。我们的初步研究目标如下：1.在小鼠模型中：确定在体内吸烟或不吸烟的病毒后小鼠模型中IL-33的功能细胞来源和靶点，并利用该模型和体外研究的相应小鼠细胞建立产生/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(使用从这些样本分离的上皮细胞)中，建立表达/释放IL-33的祖细胞群体的存在，该群体与COPD患者在基线和病毒诱导的病情恶化期间的过度粘液产生有关。这些研究将测试我们提出的从特定上皮祖细胞群表达和释放IL-33的建议，该上皮祖细胞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，以及 从而导致恶性循环，吸烟和感染导致长期过量的粘液产生。

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.