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.