Dach1 attenuates airway inflammation in chronic obstructive pulmonary disease by activating Nrf2 signaling

Background: Chronic obstructive pulmonary disease (COPD)is a small airway chronic inflammatory disease with impaired lung function primarily induced by cigarette smoke (CS). Reduced Dach1 expression has a vicious role in numerous disorders. but its role in COPD is rarely known. This study aims to elucidate the role and underlying mechanism of Dach1 in airway inflammation of COPD. Methods:Dach1 expression in lung tissues of COPD patients has been calculated. Small airway epithelium-specific Dach1 knockdown mice and AAV-transfected Dach1 overexpressed mice were used to explore its role and potential for therapeutic targeting in experimental COPD induced by CS. Furtherly, we uncovered the promising mechanism of Dach1 in inflammation induced by cigarette smoke extract simulation (CSE) in vitro. Results:The expression of Dach1 decreased in COPD patients compared to non-smokers and smoker without COPD, especially in small airway epithelium. Small airway epithelium-specific Dach1 knockdown aggravated mice airway inflammation and lung function decline caused by CS, while Dach1 overexpression protected mice from airway inflammation and lung function decline. In 16 HBE cells, Dach1 knockdown and overexpression promoted and inhibited the secretion of IL-6 and IL-8 after simulation of CSE, respectively. Nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as novel downstream target of Dach1, which directly binds to its promoter. Induction of Dach1 alleviated inflammation by activating Nrf2 signaling. Conclusions: Dach1 is decreased in COPD patients. Dach1 has protective effects against inflammation induced by CS by activating Nrf2 signaling pathway. Targeting Dach1 is a potential therapeutic strategy for COPD.