ABSTRACT: With the incessant challenge of exposure to the air we breathe, lung tissue suffers the highest levels of oxygen tension and thus requires robust antioxidant defenses. Furthermore, following injury or infection, lung tissue faces the additional challenge of inflammation-induced reactive oxygen and nitrogen species (ROS/RNS). Little is known about the identity or distribution of lung antioxidant enzymes under normal conditions or during infection-induced inflammation. Using a mouse model of influenza (H1N1 influenza virus A/PR/8/34 [PR8]) in combination with bioinformatics, we identified seven lung-abundant antioxidant enzymes: Glutathione peroxidase 3 (Gpx3), Superoxide dismutase 3 (Sod3), Transferrin (Tf), peroxyredoxin6 (Prdx6), glutathione S-transferase kappa 1 (Gstk1), Catalase (Cat), and Glutathione peroxidase 8 (Gpx8). Interestingly, despite the demand for antioxidants during inflammation, influenza caused depletion in two key antioxidants: Cat and Prdx6. As Cat is highly expressed in Clara cells, virus-induced Clara cell loss contributes to the depletion in Cat. Prdx6 is also reduced due to Clara cell loss, however there is a coincident increase in Prdx6 levels in the alveoli, resulting in only a subtle reduction of Prdx6 overall. Analogously, Gpx3 shifts from the basement membranes underlying the bronchioles and blood vessels to the alveoli, thus maintaining balanced expression. Taken together, these studies identify key lung antioxidants and reveal their distribution among specific cell types. Furthermore, results show that influenza depletes key antioxidants, and that in some cases there is coincident increased expression, consistent with compensatory expression. Given that oxidative stress is known to be a key risk factor during influenza infection, knowledge about the antioxidant repertoire of lungs, and the spatio-temporal distribution of antioxidants, contributes to our understanding of the underlying mechanisms of influenza-induced morbidity and mortality.
