Table 2.

Autophagy and mitophagy in COPD

Experimental Models of COPD	Evidence of Altered Autophagy	Protective Effect of Autophagy on COPD	Reference
Primary bronchial epithelial cells exposed to CSE	While PINK1 levels and LC3B colocalization with the mitochondria were elevated, PARKIN levels were significantly decreased in the lungs and small airway epithelial cells of COPD patients	Silencing of Pink1 or Parkin in human bronchial epithelial cells enhanced cellular senescence, suggesting a beneficial role of PARKIN and PINK1 in airway epithelial cells in attenuating cell senescence	Ito et al. 2015
	Primary bronchial epithelial cells exposed to CSE exhibited transient increase of autophagic flux. Prolonged exposure-induced accumulation of ubiquitinated proteins and p62, cell senescence and IL-8 secretion.	Lc3 silencing exacerbated the accumulation of ubiquitinated proteins and IL-8 release, and autophagy activation by Torin1, an mTOR inhibitor, suppressed accumulation of ubiquitinated proteins and senescence. These observations are consistent with a beneficial role of autophagy.	Fujii et al. 2012
Exposure of human lung fibroblasts to 0.5% CSE for 10–15 days	CS impaired mitophagy as evident by impaired mitochondrial localization to autophagosome, increased perinuclear localization of mitochondria, and increased mitochondrial DNA damage.	Mitochondrial fission inhibitor, Mdivi-1, increased cellular senescence. PARKIN overexpression or Mito-TEMPO decreased cellular senescence.	Ahmad et al. 2015
Alveolar macrophages from smokers with >10 pack a year of smoking history	Macrophages had defective autophagy, as evidenced by decreased protein degradation, increased autophagic vesicles on electron microscopy, impaired trafficking of autophagosomes to the lysosome (autophagic flux), blocked delivery of ubiquitin binding chaperone protein, p62, to the lysosome, and accumulated aggregates of ubiquitin and SUMO-modified proteins.	In this case, it was implied that autophagy is beneficial	Monick et al. 2010
Human macrophages and lungs of COPD patients	Decreased SIRT1 level in macrophages and lungs of COPD patients and in MonoMac6 cells exposed to CSE.	Sirt1 knockout mice exhibited more increase of LC3-II in response to CS.	Hwang et al. 2010
MonoMac6 and H292 cells exposed to CSE	H292 cells, SIRT1 activation by resveratrol decreases CSE-induced LC3-II, and SIRT1 inhibition by sirtinol enhances CSE-induced LC3-II.
Human lung homogenates from COPD patients	SIRT6 levels are decreased. Sirt6 overexpression increased LC3-II while siRNA of Sirt6 decreased LC3-II, correlating with suppressed and enhanced senescence, respectively suggesting a protective role of SIRT6.	Not assessed	Takasaka et al. 2014
Human bronchial epithelial cells exposed to CSE
Beas-2b cells exposed to CSE	Not assessed	Carbamazepine decreases CSE-induced perinuclear accumulation of ubiquitinated proteins	Lin et al. 2013
	LacCer-synthase inhibitor decreased p62 accumulation in response to CSE	Not assessed	Guo et al. 2013

Experimental Models of COPD	Evidence of Altered Autophagy	Detrimental Effect of Autophagy on COPD	Reference
Whole lungs from smoking patients; Epithelial cells or fibroblasts exposed to CSE; Mice exposed to CS	Increased LC3B-II/I ratio, ATG4, ATG5-ATG12, and ATG7 proteins, increased autophagosome vacuoles in COPD patients. Egr-1−/− mice are resistant to cigarette smoke-induced apoptosis and emphysema.	In human pulmonary epithelial cells, knockdown of Egr-1 inhibited CSE-induced LC3B and ATG4B expression. Inhibition of autophagy by Lc3b knockdown protected epithelial cells from CSE-induced apoptosis.	Chen et al. 2008
	Ho-1 overexpression inhibited the increase of LC3B-II or BECN1, the activation of DISC and the activation of caspase 3, 8, and 9. Ho-1 siRNA augmented DISC activation.	Both Lc3b and Becn siRNA decreased activation of caspase 3 and 8 in Beas-2b cells.	Kim et al. 2008
	Nrf2 siRNA increases, while and N-acetylcysteine, Keap1 siRNA, Nrf2 overexpression, or p62 overexpression decreases LC3B-II.	Not assessed	Zhu et al. 2013
	LC3B dissociation from Fas might be responsible for induction of apoptosis in response to CS or CSE.	Knockout Cav-1 which mediates LC3B-Fas association exacerbates CS exposure-induced apoptosis.	Chen et al. 2010
	Increased LC3B in COPD patients, associated with higher TLR4.	Tlr4−/−mice exhibited higher LC3B and augmented emphysema.	An et al. 2012
Human LMVEC from smokers and nonsmokers	LMVEC from smokers were resistant to ceramide-induced apoptosis. Treatment of cells with ceramide increased LC3B-II/I and increased autophagosomes, regardless of the smoking status of the donor.	Cells from smokers are resistant to 3-MA-induced caspase-3 activation.	Petrusca et al. 2014
Mice exposed to CS	Not assessed	Deficits in mucociliary clearance and cilia shortening are exacerbated by Nrf2 knockout and attenuated by Becn, Lc3b, and Hdac6 disruption, or chemical chaperone 4-phenylbutyric acid.	Lam et al. 2013
Exposure of human bronchial epithelial cells to 20% aqueous CSE for 4 h	In CSE-exposed cells there was an increased transportation of mt-mKeima to the lysosomes, indicating increased mitophagy.	Pharmacological inhibition of mitochondrial fission by Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro. Genetic disruption of PINK1 increased mucociliary clearance and protected against mitochondrial depolarization.	Mizumura et al. 2014