ROMO1 is involved in airway mucus hypersecretion in COPD through the mitochondrial ROS-STAT6 pathway

Background: Oxidative stress contributes to airway mucus hypersecretion in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although reactive oxygen species modulator 1 (ROMO1) is involved in mitochondrial oxidative stress, its role in airway mucus hypersecretion in COPD remains unclear. Methods: The protein expression of ROMO1 and mucin5AC (MUC5AC) in human airway epithelium was determined by immunohistochemistry. The effects of ROMO1 on mitochondrial injury and MUC5AC expression in cigarette smoke extract (CSE)-treated airway epithelial cells were evaluated by a series of experimental techniques, including real-time PCR, western-blot and immunofluorescent staining. Results: Protein expression of ROMO1 and MUC5AC was significantly elevated in the airway epithelium of COPD patients compared with the controls. The mRNA and protein expression of ROMO1 and MUC5AC were significantly increased in concentration- and time-dependent manners when airway epithelial cells were treated with CSE. ROMO1 silencing significantly suppressed 7.5% CSE-induced mitochondrial structure damage, mitochondrial membrane potential loss, intracellular ATP depletion, mitochondrial reactive oxygen species production, signal transducer and activator of transcription 6 (STAT6) phosphorylation, and MUC5AC expression in airway epithelial cells. Moreover, pretreatment with either a mitochondrial-targeted antioxidant or STAT6 inhibitor significantly inhibited the up-regulated expression of p-STAT6/STAT6 and MUC5AC in airway epithelial cells stimulated with 7.5% CSE. Conclusion: Our findings suggest that ROMO1 contributes to airway mucus hypersecretion in COPD by mediating MUC5AC expression in airway epithelial cells via the mitochondrial ROS-STAT6 pathway, thereby highlighting its potential clinical value as a therapeutic target.