Pathogenesis of mucous cell metaplasia in ozone-exposed airways

臭氧暴露气道粘液细胞化生的发病机制

• 批准号: 10598728
• 负责人: Yogesh Saini
• 金额: $ 22.04万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-06 至 2023-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598728
• 关键词: AREG gene; Ablation; Air Pollution; Apoptotic; Asthma; Basal Cell; CASP3 gene; Cell Death; Cell Proliferation; Cells; Child; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Cities; Clinical; Cystic Fibrosis; DTR gene; Data; Defect; Development; EGF gene; Elderly; Environment; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Escalator; Gene Expression; Genes; Genetic; Hospitalization; IL13RA1 gene; Immune; Immunoassay; Interleukin-13; Interleukin-4; Knowledge; Lead; Ligands; Ligation; Lung diseases; MUC5B gene; Metaplasia; Modeling; Molecular; Molecular Profiling; Monitor; Motor Vehicles; Mucous body substance; Mus; Nose; Ozone; Pathogenesis; Pathway interactions; Patients; Phenotype; Pollution; Production; Proteins; Publishing; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Sendai virus; Signal Pathway; Signal Transduction; Smog; Stains; Stress; Symptoms; Techniques; Testing; Vehicle Emissions; airway epithelium; cell injury; cystic fibrosis patients; epithelial injury; inflammatory marker; keratin 5; mRNA Expression; muco-obstructive airway diseases; ozone exposure; pulmonary function; pulmonary symptom; receptor; respiratory; therapeutic development; therapeutically effective; transdifferentiation

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.

摘要：环境臭氧水平升高与呼吸系统疾病导致的住院率增加有关。 儿童、老年人和患有粘液阻塞性气道疾病的患者的问题。 粘膜阻塞性气道疾病经常遇到臭氧污染引起的病情加重，并伴有明显的症状 粘液分泌过多和粘液阻塞会导致临床症状恶化。 然而，对肺功能的发生和进展的机制的理解。 臭氧应激的呼吸道上皮中的粘液细胞化生（MCM）仍未被探索。 知识是制定针对臭氧加剧的有效治疗策略的主要障碍 我们发表的初步数据揭示了粘膜阻塞性气道疾病之间的有趣关系。 首先，重复接触臭氧会导致健康小鼠出现 MCM。其次，重复接触臭氧会导致 MCM。 暴露会加剧患有慢性支气管炎样肺的小鼠的 MCM 和粘膜阻塞表型 这些发现表明臭氧引起粘液阻塞性肺部症状恶化。 患者的部分原因是夸大的 MCM 和相关的功能缺陷 我们的初步数据表明，虽然 Il4ra 受体的 mRNA 表达和 其配体 IL-13 的分泌水平在亚慢性（3 周）气道中显着上调 臭氧暴露小鼠中，Egfr 及其配体 Tgfa 的 mRNA 表达显着下调。 这些数据表明臭氧诱导的 MCM 中 EGFR 和 IL4Rα 信号通路的差异调节。 因此，机械地测试 EGFR 与 IL4Rα 调节途径在臭氧中的作用非常重要。 因此，我们的中心假设是臭氧诱导的 MCM 不依赖于 EGFR。 信号传导，但依赖于 IL4Rα 信号传导，调节气道上皮细胞的转分化 具体目标是： 目标 1：描绘 MCM 转分化途径并进行分析。 与暴露于臭氧的小鼠气道中的 MCM 相关的分子和细胞变化 为了实现这一目标，我们将。 暴露于臭氧的鼻腔和下呼吸道中与 MCM 相关的细胞和分子变化 目标 2：确定基底细胞与上皮细胞特异性 EGFR 和 IL4Rα 在基底细胞中的作用。 气道上皮细胞特异性 EGFR 和 IL4Rα 缺陷小鼠将用于研究其配体的作用 我们的研究结果将增强我们对臭氧引起的 MCM 的机制的理解。 最终，这些发现可能会应用于 MCM 的开发。 针对空气污染引起的 MCM 的治疗方法。