Pathogenesis of mucous cell metaplasia in ozone-exposed airways

摘要：环境臭氧水平升高与呼吸系统疾病引起的住院治疗增加有关。 儿童、老年人和既存粘膜阻塞性气道疾病患者的问题。患者 粘膜阻塞性气道疾病经常遇到臭氧污染引起的恶化， 粘液分泌过多和粘膜阻塞。这些特征导致临床症状恶化， 肺功能进一步下降。然而，对启动和进展的机械理解， 臭氧应激呼吸道上皮中的粘液细胞化生（MCM）仍然未被探索。缺乏这种 知识是发展有效的治疗战略，防止臭氧加剧的一个主要障碍， 粘膜阻塞性气道疾病。我们公布的和初步的数据揭示了有趣的关系， 臭氧和MCM。首先，重复的臭氧暴露导致健康小鼠的MCM。二、重复臭氧 暴露可加重慢性支气管炎样肺小鼠的MCM和粘膜阻塞表型 疾病这些发现表明，臭氧引起的肺部症状加重的粘膜阻塞性肺疾病， 患者的部分原因是夸大的MCM和相关的功能缺陷， 粘液纤毛自动梯我们的初步数据表明，虽然IL-4 ra受体和IL-14受体mRNA的表达， 其配体IL-13的分泌水平在亚慢性（3周） 臭氧暴露小鼠，Egfr及其配体（即，Tgfa显著下调。 这些数据表明，EGFR和IL 4 R β信号通路的差异调节臭氧诱导的MCM。 因此，重要的是从机制上测试EGFR与IL 4 R β调节途径在臭氧中的作用。 MCM暴露模型。因此，我们的中心假设是，臭氧诱导的MCM是独立的EGFR 信号转导，但依赖于调节气道上皮细胞转分化为 粘液细胞具体目的如下：目的1：阐明MCM转分化途径， 臭氧暴露小鼠气道中与MCM相关的分子和细胞变化。为此，我们会 暴露于臭氧的鼻和下气道中与MCM相关的细胞和分子变化 小鼠目的2：确定基底细胞与上皮细胞特异性EGFR和IL 4 R β在MCM中的作用。基底细胞- 和气道上皮细胞特异性EGFR和IL 4 R β缺陷小鼠将用于研究其配体的作用。 在臭氧诱导MCM中。我们的研究结果将增强我们对 分子途径参与MCM。最终，这些发现可能会应用于开发 治疗空气污染引起的MCM。

Summary: Elevated ambient ozone levels are associated with increased hospitalizations due to respiratory problems in children, the elderly, and patients with pre-existing muco-obstructive airway diseases. Patients with muco-obstructive airway diseases frequently encounter ozone pollution-induced exacerbations with marked overproduction of mucus and mucoobstruction. These features lead to the worsening of clinical symptoms and further decline in lung functions. However, the mechanistic understanding of the initiation and progression of mucous cell metaplasia (MCM) in ozone-stressed respiratory epithelium remains unexplored. Lack of such knowledge is a major obstacle in the development of effective therapeutic strategies against ozone-exacerbated muco-obstructive airway diseases. Our published and preliminary data reveal interesting relationship between ozone and MCM. First, repetitive ozone exposure results in MCM in healthy mice. Second, repetitive ozone exposure exaggerates MCM and mucoobstructive phenotype in mice with ongoing chronic bronchitis-like lung disease. These findings suggest that ozone-induced exacerbations of pulmonary symptoms in muco-obstructive patients are contributed, in part, by exaggerated MCM and associated defects in the functioning of the mucociliary escalator. Our preliminary data demonstrate that while the mRNA expression of Il4ra receptor and the secretory levels of its ligand, IL-13, were significantly upregulated in the airways of sub-chronically (3-week) ozone-exposed mice, the mRNA expression of Egfr and its ligands, i.e., Tgfa, were significantly downregulated. These data indicate differential regulation of EGFR and IL4R signaling pathways in ozone-induced MCM. Therefore, it is important to mechanistically test the role of EGFR- versus IL4R-regulated pathways in ozone- exposed model of MCM. Accordingly, our central hypothesis is that ozone-induced MCM is independent of EGFR signaling but dependent upon IL4R signaling that regulates the transdifferentiation of airway epithelial cells to mucous cells. The specific aims are: Aim 1: To delineate MCM transdifferentiation pathway and to profile molecular and cellular changes associated with MCM in ozone-exposed murine airways. In this aim, we will profile cellular and molecular changes associated with MCM in the nasal and lower airways of ozone-exposed mice. Aim 2: Determine the role of basal- versus epithelial cell-specific EGFR and IL4R in MCM. Basal cell- and airway epithelial cell-specific EGFR- and IL4R-deficient mice will be used to study the role of their ligands in ozone-induced MCM. The findings from our studies will enhance our mechanistic understanding of the molecular pathways involved in MCM. Eventually, these findings may be applied towards the development of therapeutics against air pollution-induced MCM.