Repetitive ozone exposure worsens features of muco-inflammatory disease in developed Scnn1b-Tg+ mice lungs

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Abstract
Introduction: Ambient exposure to ozone (O3), one of the six criteria pollutants, is associated with the exacerbation of respiratory symptoms in individuals with underlying lung diseases. Using Scnn1b-Tg+ (Tg+) mice, a widely used model of muco-inflammatory lung disease, we have demonstrated that O3 exposure during the early stages of postnatal lung development leads to exacerbated muco-inflammatory outcomes. However, it remains unclear whether O3 affects the developed lungs differently than the underdeveloped lungs of Tg+ mice.Methods: We exposed 3-week-old wild-type (WT) and Tg+ mice to either filtered air (FA) or 0.8 ppm O3 for 3 weeks and examined the lung phenotypes 12-16 h post-last exposure.Results: As compared to FA-exposed WT mice, O3-exposed WT mice showed increased bronchoalveolar lavage fluid (BALF) proteins, increased immune cells, increased inflammation, alveolar space enlargement, and tissue consolidation. As compared to FA-exposed WT mice, the FA-exposed Tg+ mice showed increased immune cells, elevated levels of inflammatory mediators, e.g., IL-5, G-CSF, MIP-2, KC, MIP-1α, MIP-1β, IP-10, TNF-α, and IL-17, increased inflammation, alveolar space enlargement, tissue consolidation. As compared to FA-exposed Scnn1b-Tg+ mice, O3-exposed Tg+ mice had increased total protein, total dsDNA, and phagocytosed lipid contents, in addition to exaggerated granulocytic recruitment, peripheral and bronchiolar inflammation, alveolar space enlargement, and tissue consolidation.Discussion: Together, our data using Tg+ mice with developed lungs exhibited several findings consistent with previous findings observed in Tg+ neonates. Interestingly, however, as opposed to the previous report in O3-exposed neonatal Tg+ mice, where the hallmark features of Tg+ airway disease, i.e., mucus obstruction and expression of major gel-forming mucins (MUC5B and MUC5AC) were found exacerbated by O3 exposure, the FA- and O3-exposed Tg+ mice with developed lungs exhibited comparable responses. These differential responses suggest that the stage of lung development is an important factor in the modulation of epithelial remodeling following O3 exposure.

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