| Abstract |
DUOX1 is a homolog of the NADPH oxidase family that is prominently expressed in epithelial cells at mucosal surfaces, including the lung. Our prior studies showed that DUOX1 participates in airway epithelial host defense against various environmental triggers, particularly by promoting epithelial release of alarmins such as interleukin-33, and by activation of type 2 immune responses that help improve epithelial regeneration and mucociliary clearance of pathogens. These processes involve DUOX1-dependent production of H2O2 and subsequent redox-dependent activation of tyrosine kinase signaling involving Src family kinases and EGFR signaling. Airway DUOX1 is increased in subjects with allergic asthma, and studies of genetic deletion or pharmacological inhibition of DUOX1 indicate their ability to prevent or reverse various key symptoms of allergic airway inflammation, such as type 2 inflammation, mucus hyperplasia, and airway remodeling, suggesting DUOX1 as a useful therapeutic target. In current ongoing work, we are extending these observations in the context of comorbities that may worsen asthma, such as obesity and aging. Intriguingly, we observed that airway DUOX1 is decreased during aging, which is associated with impaired innate epithelial type 2 responses upon injury, and suggest that such DUOX1 decline may contribute to increased susceptibility to age-related diseases such as chronic obstructive pulmonary disease or pulmonary fibrosis. In this presentation, I will briefly summarize the history of discovery of NADPH oxidases such as DUOX1, and the varying roles of DUOX1 in lung biology and pathology, which highlight some unanticipated twists and potential expanded therapeutic opportunities of DUOX1 targeting. |
