FBXO11 deficiency in mice impairs lung development and aggravates cigarette smoke-induced airway fibrosis

Small airway fibrosis is a common pathology of chronic obstructive pulmonary disease (COPD) and contributes to airflow obstruction. However, the underlying fibrogenic mechanism is poorly understood. Epithelial-mesenchymal transition (EMT) has been proposed as a driver of fibrosis. EMT occurs in the airways of COPD patients and smokers, but it remains elusive whether EMT may contribute to airway fibrosis. We previously reported that FBXO11 is a critical suppressor of EMT and Fbxo11 deficiency in mice causes neonatal lethality and EMT in epidermis. Here, we found that Fbxo11-deficient mouse embryonic lungs showed impaired epithelial differentiation, excess fibroblast cells surrounding the airways, and thickened interstitial mesenchyme. We further generated conditional mutant mice to ablate Fbxo11 selectively in the club airway epithelial cells in adult mice, which induced partial EMT in the airways. To determine the effect of EMT on airway fibrosis, Fbxo11 conditional mutant mice were exposed to cigarette smoke. Airway-specific loss of Fbxo11 markedly enhanced smoking-induced airway fibrotic remodeling and collagen deposition. Taken together, our study suggests that EMT in the airway epithelium exacerbates cigarette smoke-induced airway fibrosis.