Chronic airway diseases such as asthma are associated with increased production of reactive oxygen species (ROS) and oxidative stress. Endogenous NADPH oxidases are a major source of superoxide in lung, but their underlying role in asthma pathology is poorly understood. We sought to characterize the involvement of NADPH oxidase in allergic asthma by studying the role of CYBA (p22phox) in human asthma and murine house dust mite (HDM)-induced allergic airway inflammation.
Results:
Increased expression and localization of p22-PHOX were observed in biopsies of asthmatic patients. HDM-treated wild-type mice possessed elevated p22phox expression, corresponding with elevated superoxide production. p22phox knockout (KO) mice did not induce superoxide and were protected against HDM-induced goblet cell hyperplasia and mucus production and HDM-induced airway hyperresponsiveness (AHR). IL-13-induced tracheal hyperreactivity and signal transducer and activator of transcription (STAT)6 phosphorylation were attenuated in the absence of p22phox or catalase pretreatment.
Innovation:
Our study identifies increased expression of p22phox in lungs of asthmatic patients and in experimental model. The induced AHR and mucus hypersecretion are a result of increased ROS from the p22phox-dependent NADPH oxidase, which in turn activates STAT6 for the pathological feature of asthma.
Conclusions:
Together with the increased p22phox expression in lungs of asthmatic patients, these findings demonstrate a crucial role of p22phox-dependent NADPH oxidase for the development of mucus hypersecretion and AHR in HDM-induced model of asthma. This suggests that inhibition of functional NADPH oxidase by selective interference of p22phox might hold a promising therapeutic strategy for the management of asthma. Antioxid. Redox Signal. 27, 1460–1472.
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