FAM13A regulates cellular senescence marker p21 and mitochondrial reactive oxygen species production in airway epithelial cells.

Abstract

Inhalation of noxious gasses induces oxidative stress in airway epithelial cells (AECs), which may lead to cellular senescence and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD). FAM13A, a well-known COPD susceptibility gene, is highly expressed in airway epithelium. We studied whether its expression is associated with aging and cellular senescence and affects airway epithelial responses to paraquat, a cellular senescence inducer. The association between age and FAM13A expression was investigated in two datasets of human lung tissue and bronchial brushings from current/ex-smokers with/without COPD. Protein levels of FAM13A and cellular senescence marker p21 were investigated using immunohistochemistry in lung tissue from COPD patients. In vitro, FAM13A and P21 expression was assessed using qPCR in air-liquid-interface (ALI)-differentiated AECs in absence/presence of paraquat. Additionally, FAM13A was overexpressed in human bronchial epithelial 16HBE cells and the effect on P21 expression (qPCR) and mitochondrial ROS production (MitoSOX staining) was assessed. Lower FAM13A expression was significantly associated with increasing age in lung tissue and bronchial epithelium. In airway epithelium of COPD patients, we found a negative correlation between FAM13A and p21 protein levels. In ALI-differentiated AECs, the paraquat-induced decrease in FAM13A expression was accompanied by increased P21 expression. In 16HBE cells, the overexpression of FAM13A significantly reduced paraquat-induced P21 expression and mitochondrial ROS production. Our data suggest that FAM13A expression decreases with aging, resulting in higher P21 expression and mitochondrial ROS production in the airway epithelium, thus facilitating cellular senescence and as such potentially contributing to accelerated lung aging in COPD.