FIG. 9.

Schematic showing cigarette smoke mediated TFEB/autophagy-impairment in COPD-emphysema. Under normal physiological conditions, the optimal inflammatory oxidative signaling restricts extracellular insults via the robust proteostasis/autophagy responses. Cigarette smoke exposure mediates ROS activation in lung epithelial cells that can induce inflammatory-oxidative stress, resulting in autophagy-impairment and formation of perinuclear aggresome-bodies that mediate COPD-emphysema pathogenesis. Moreover, CS-induced perinuclear accumulation of TFEB, the master autophagy regulator, in aggresome-bodies hampers autophagy responses in COPD-emphysema. TFEB inhibition induces ROS activity, resulting in aggresome-formation and cellular senescence/apoptosis, while treatment with TFEB-inducing antioxidant drugs (GEM or FIS) controls CS-induced inflammatory-oxidative stress, aggresome pathology, and alveolar apoptosis. Overall, smoke exposure impairs TFEB/autophagy activity, resulting in downstream functional changes associated with progression of COPD-emphysema pathophysiology. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars