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：较高的环境臭氧水平与呼吸道的住院增加有关 儿童，老年人和患有粘液刺激性气道疾病的患者的问题。患者 粘膜刺激性气道疾病经常遇到臭氧污染引起的加剧，并明显 粘液和粘液结构过量生产。这些功能导致担心临床症状和 肺功能进一步下降。但是，对主动性和进步的机械理解 臭氧压力呼吸道上皮中的粘液细胞化生（MCM）仍然出乎意料。缺乏这样的 知识是开发有效的治疗策略反对臭氧的主要障碍 粘膜刺激性气道疾病。我们发布的初步数据揭示了有趣的关系 臭氧和MCM。首先，在健康小鼠中，重复的臭氧暴露会导致MCM。其次，重复的臭氧 暴露夸大了持续类似慢性支气管炎的小鼠的MCM和粘液结构表型 疾病。这些发现表明，臭氧引起的肺泡症状加重 患者的部分原因是夸张的MCM和相关的缺陷 粘毛自动扶梯。我们的初步数据表明，虽然IL4RA受体的mRNA表达和 其配体IL-13的分泌级别在亚平均（3周）的气道中显着更新 臭氧暴露的小鼠，EGFR及其配体的mRNA表达，即TGFA，显着下调。 这些数据表明臭氧诱导的MCM中EGFR和IL4R信号通路的差异调节。 因此，重要的是要机械测试EGFR-与IL4R调节的途径在臭氧 - MCM的暴露模型。彼此之间，我们的中心假设是臭氧诱导的MCM独立于EGFR 信号传导，但取决于调节气道上皮细胞转分化的IL4R信号传导 粘液细胞。具体目的是：目标1：描绘MCM跨分化途径并剖面 与MCM相关的分子和细胞变化在暴露于臭氧的鼠气中。在这个目标中，我们将 与臭氧暴露的鼻和较低气道中与MCM相关的细胞和分子变化 老鼠。 AIM 2：确定MCM中基底和上皮细胞特异性EGFR和IL4R的作用。基础细胞 和气道上皮细胞特异性EGFR-和IL4R缺乏小鼠将用于研究其配体的作用 在臭氧引起的MCM中。我们研究的发现将增强我们对 MCM中涉及的分子途径。最终，这些发现可能用于发展 针对空气污染引起的MCM的治疗剂。