Thus, autophagy plays a vital role in limiting lung infections, and it is evident that a complete or partial absence of functional CFTR leads to autophagy impairment. Mechanistically, CFTR loss or dysfunction results in the reactive oxygen species (ROS)-mediated activation of transglutaminase-2 (TGM-2), and inactivation of the Beclin-1 complex, thereby causing autophagy impairment [61]. Apart from the genetic loss or dysfunction of CFTR, exposure to CS also leads to decreased CFTR activity and expression in vitro, in animal models and in smokers with or without COPD, primarily via ROS-dependent mechanisms [22,42,62,63]. This acquired CFTR dysfunction results in increased inflammatory-oxidative stress, apoptosis, cellular senescence, defective autophagy, and impaired mucociliary clearance, all hallmarks of COPD.