4.4. Autophagy Defects in COPD
We and others have described autophagy dysfunction as a prime causative factor utilizing in vitro and animal models of smoke- (cigarette and waterpipe) or eCV (nicotine)-induced lung injury and COPD-emphysema [33,34,39,94,109]. Moreover, these were validated in human subjects where defective autophagy was verified using human lung tissues from COPD-emphysema subjects, where classical autophagy impairment features, such as aggresome bodies, were associated with the severity and progression of the disease [22,36]. These aggresome bodies are perinuclear accumulations of misfolded or aggregated proteins, which are poly-ubiquitinated and co-localize with p62 and the autophagy protein microtubule-associated protein 1 light-chain-3B(+) (LC3B+) bodies, and are the key indicators of defective autophagy flux [33,36,143]. Additionally, we and others have also noted the increase in aggresome body formation in aged mice lungs that correlated with alveolar airspace enlargement (emphysema phenotype), indicating that age-related decline in autophagy contributes to COPD-emphysema development, similar to CS exposure [33]. Moreover, an increase in emphysema severity (GOLD 0-IV) in smokers with a minimal age difference [33] also correlated with an increase in alveolar senescence, indicating the presence of accelerated lung aging in severe COPD-emphysema subject lungs. We further validate smoke-induced accelerated lung aging using aging markers and in vitro and murine models of COPD-emphysema. In further studies, a clear mechanistic and protective role of TFEB, the master autophagy regulator, was observed in CS-induced lung disease models where other pathogenic features of COPD-emphysema, such as inflammatory-oxidative stress, senescence, apoptosis, and aggresome formation, were used for the validation of pathogenic roles [34,35]. In fact, the CS-induced sequestration of TFEB protein into aggresome bodies leads to its decreased availability, which prevents its function as a transcription factor to positively regulate the autophagy process [34,35]. Moreover, TFEB-mediated autophagy was shown to be protective against oxidative stress and hepatotoxicity induced by ethyl carbamate (a toxicant in CS) [144], suggesting that TFEB-autophagy is a protective mechanism against CS exposure-induced toxicity, not only in the lungs, but in other vital organs as well. Additionally, TFEB-mediated autophagy has also been shown to control CS-induced cellular senescence, and bacterial phagocytic clearance, thus highlighting its protective role in CS-induced COPD-emphysema [22,34,35]. In addition to TFEB, other mechanistic mediators of autophagy have been shown to participate in the sequential dysfunction or impairment of autophagy processes, contributing as a key mediator of COPD-emphysema pathogenesis. For example, increased levels of bicaudal D1 (BICD1), an adaptor for the dynein–dynactin motor complex, were found in the peripheral lung tissues of COPD patients, which was associated with increased p62 oligomers [145]. Additionally, the exposure of bronchial epithelial cells or mice to CS led to increased BICD1 levels, along with defective autophagosome maturation, and an accumulation of BICD1 with p62 and ubiquitin-associated p62-oligomers, thus confirming the mechanistic role of BICD1 in CS-induced autophagy defects [145].
Dysfunctional autophagy has also been associated with defects in specific cell types of the airway. The secretory cells of the airway, such as the club and goblet cells, play an important role in host defense during infection. Autophagy has been recently shown to be required to maintain the function of club cells, independent of CS exposure [146]. Mice deficient in autophagy protein Atg5, demonstrate a diminished expression of the host defense protein secretoglobulin family 1A member 1 (SCGB1A1) and surfactant proteins A1 and D (Sftpa1 and Sftpd), as well as abnormal club cell morphology [146]. Moreover, a diminished SCGB1A1 expression in club cells correlates with evidence of reduced autophagy in lung tissue from COPD former smokers [146]. CS exposure has also been demonstrated to cause the accumulation of damaged mitochondrial via impaired mitophagy, which has been demonstrated to play a role in COPD pathogenesis disease progression [147,148]. Thus, it can be postulated that CS-induced autophagy dysfunction would further deteriorate the structure and function of club cells, resulting in altered or diminished host defense mechanisms in COPD subjects.