Postnatal ozone exposure disrupts alveolar development, exaggerates mucoinflammatory responses, and suppresses bacterial clearance in developing Scnn1b-Tg+ mice lungs.

Abstract

Abstract Increased levels of ambient ozone result in the respiratory tract injury and worsening of ongoing lung diseases. However, the effect of ozone exposure on the respiratory tract undergoing active lung development and simultaneously experiencing mucoinflammatory lung diseases such as cystic fibrosis (CF) remains unclear. To address these questions, we exposed sodium channel non-voltage gated 1, beta subunit overexpressing transgenic mice (Scnn1b-Tg+), a mouse model of CF-like lung disease, and littermate wild type (WT) mice to ozone from postnatal day (PND) 3–20 and examined the lung phenotypes at PND21. As compared to filtered air (FA)-exposed WT mice, the ozone-exposed WT mice exhibited marked alveolar space enlargement, significant eosinophilic infiltration, type-2 inflammation, and mucous cell metaplasia. Ozone-exposed Scnn1b-Tg+ mice also exhibited significantly increased alveolar space enlargement, exaggerated granulocytic infiltration, type-2 inflammation, and greater degree of mucoobstruction. The alveolar space enlargement in ozone-exposed WT, and ozone-exposed Scnn1b-Tg+ mice was accompanied by elevated levels of MMP12 protein in macrophages and Mmp12 mRNA in the lung homogenates. Finally, while bacterial burden was largely resolved by PND21 in FA-exposed Scnn1b-Tg+ mice, ozone-exposed Scnn1b-Tg+ mice exhibited compromised bacterial clearance which was also associated with increased levels of IL-10, an immunosuppressive cytokine, and marked mucoobstruction. Taken together, our data show that ozone exposure results in alveolar space remodeling during active phases of lung development and markedly exaggerates the developmental history of an ongoing mucoinflammatory pediatric onset lung disease.