Lysosomal dysfunction in COPD pathogenesis

Introduction: Lysosomal dysfunction has been linked to the pathogenesis of age-related diseases. Lysosomal integrity is orchestrated through not only biogenesis but also selective autophagic degradation, lysophagy. Cigarette smoke extract (CSE) induces lipofuscin accumulation, which may reflect lysosomal dysfunction along with cellular senescence in lung epithelial cells. Although accelerated cellular senescence has been widely implicated in COPD pathogenesis, involvement of altered lysosomal integrity regulated by lysophagy remains uncertain. Methods: Using human lung tissues and bronchial epithelial cells (HBEC) isolated from normal and COPD lungs, immunohistochemical staining and western blotting (WB) were performed to evaluate LAMP1, Galectin-3, and TRIM16 expression levels. Lipofuscin was detected by Schmorl staining. Aggresome formation was examined by using detection kit. SiRNA-mediated knockdown experiments were performed to elucidate the role of TRIM16 in lysophagy. Results: Schmorl staining showed increase in lipofuscin positive epithelial cells in COPD lungs. LAMP1 and Galectin-3 expression levels were upregulated and electron microscopic evaluation showed increase in number of lysosomes in COPD lungs. Accumulation of aggresome, reflecting insufficient lysosomal degradation was also detected. TRIM16, a platform for autophagic initiation during lysophagy, was reduced in COPD. TRIM16 knockdown significantly enhanced CSE-induced ROS production, aggresome formation, and cellular senescence in HBEC. Conclusion: These findings suggest that accumulation of dysfunctional lysosome, which is attributed to reduced TRIM16-mediated lysophagy, can be associated with enhanced epithelial cell damage during COPD pathogenesis.