64 - Progressive loss of dual oxidase 1 (DUOX1) contributes to impaired airway epithelial wound responses in the aging lung

Abstract

Age-related chronic diseases, including chronic respiratory diseases such as COPD, are associated with organ function decline, impaired regenerative capacity, and immuno-senescence. Our recent studies indicate that such reparative processes in the lung are mediated by innate epithelial injury responses and production of reactive oxygen species (ROS) by the NADPH oxidase dual oxidase 1 (DUOX1), which were found to be associated with oxidation and activation of epithelial tyrosine kinases, such as epidermal growth factor receptor (EGFR) and the non-receptor tyrosine kinase Src, and also with epithelial secretion of alarmins such as IL-33, which promote epithelial regeneration by activating type 2 immune responses. Contrasting the common belief that aging is associated with increased ROS production, we observed that DUOX1 expression in mouse lungs markedly decreases with age. Moreover, we noticed that DUOX1-deficient mice display accelerated age-related decline in lung function and features of emphysema, as shown by airspace enlargement and increased lung compliance. We hypothesized that loss of DUOX1 may contribute to other features of lung aging, but aged-related lung changes such as increased parenchymal collagen deposition, molecular indices of senescence, or tissue levels of pro-inflammatory cytokines, were all largely unaltered in DUOX1-deficient mice. However, we observed that aged mice display markedly attenuated innate airway responses to inhaled allergens, as illustrated by diminished secretion of IL-33 and other related cytokines. Similar findings were observed in vitro using cultured mouse tracheal epithelial cells (MTEC), in which MTECs from older mice showed dramatically reduced innate responses to injury, which was associated with reduced oxidation and activation of Src and EGFR. Consistent with a potential age-related suppression of DUOX1 by epigenetic mechanisms such as promoter hypermethylation, allergen-induced IL-33 secretion in MTECs from aged mice could be rescued by treatment with the DNA methyltransferase inhibitor AzdC. Overall, these results underline the importance of DUOX1 in airway host defense and regenerative capacity, and indicate that age-related loss of DUOX1 contributes to accelerated impairment of epithelial regenerative capacity and air-space enlargement.