Thursday, April 18, 2024
4/18/2024
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.
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