Genomic instability | γ-H2A.X | ↑ | Lung tissue sections, AT1, AT2, HBEC and PV-EC | HBEC, HFL1 and MRC-5 | [75, 76, 78, 79] |
Ku70 | ↓ | Peripheral leukocytes | | [80] |
Ku80 | ↓ | Lung homogenates | | [77] |
Telomere shortening | Length | ↓ | Lung homogenates AT2, PA-SMC, PV-EC and peripheral leukocytes | SAEC (COPD) and HFL1 | [78, 81–86] |
Telomerase | ↓ | PV-EC | | [84] |
TPP1 | ↓ | Lung homogenates | SAEC and HFL1 | [78] |
Epigenetic changes | HDAC activity | ↓ | Lung homogenates and bronchial biopsies | | [92] |
SIRT1 and -6 | ↓ | Lung homogenates | | [94, 95] |
Loss of proteostasis | Autophagy | ↑ | HBEC | SAEC | [100] |
Autophagy | ↓ | | HBEC (COPD) | [100] |
Autophagosomes | ↑ | Lung homogenates | HBEC and BEAS-2B | [79, 99, 100] |
Ubiquitin | ↑ | Lung homogenates | | [98, 100] |
p62 | ↑ | Lung homogenates | | [79, 100] |
Deregulated nutrient sensing | S6K (mTOR) | ↑# | Lung homogenates and peripheral leukocytes | HBEC | [79, 103] |
IGF1 | ↑ | SAEC | | [104] |
Mitochrondrial dysfunction | ROS | ↑ | | HBEC, BEAS-2B and MRC-5 | [76, 108, 109] |
Oxidised DNA | ↑ | Lung homogenates | | [77] |
Lipid peroxidation | ↑ | Lung homogenates | | [105, 106] |
Nitric oxide | ↑ | Lung homogenates | | [106] |
Mitophagy | ↑ | Lung homogenates | HBEC and BEAS-2B | [108, 109] |
Antioxidant | ↓ | Lung homogenates and HBEC | | [107] |
Mitochondrial membrane potential | ↓ | | BEAS-2B | [108] |
Immune dysregulation | Klotho | ↓ | Lung homogenates | HBEC | [112] |
NF-κB | ↑ | Lung homogenates | | [113] |
Pro-inflammatory cytokines | ↑ | Lung homogenates | | [113] |
Senescence | SA-β-gal | ↑ | SAEC, PA-SMC, PV-EC and fibroblasts | SAEC (COPD), HBEC, A549, HFL1 and MRC-5 | [76, 78, 79, 84–86, 115–117] |
p16 | ↑ | Lung tissue sections, AT1, AT2, PA-SMC, PV-EC and fibroblasts | HFL1 | [75, 76, 78, 84–86, 116, 117] |
p21 | ↑ | Lung homogenates, AT2, PA-SMC, PV-EC and peripheral leukocytes | HBEC, A549 and HFL1 | [78–80, 84–86, 117] |
IL-6 and IL-8 | ↑ | Lung tissue sections, AT1, AT2, PA-SMC and PV-EC | MRC-5 | [75, 76, 84, 85] |
ECM dysregulation | ECM proteins | ↑ | Lung homogenates | | [42] |
Elastogenesis genes | ↑ | Lung homogenates | | [125] |
MMP/TIMP dysregulation | ↑ | Lung homogenates | | [123] |
Stem cell exhaustion | Circulating progenitor cells | ↓# | Endothelial and haemopoietic progenitor cells | | [137, 138] |
Regenerative capacity | ↓ | Basal progenitor cells | | [135] |
Stem cell function | ↓ | HBEC | | [142] |
WNT signalling | ↓# | Lung homogenates, AT2 and SAEC | | [144, 147] |
Notch pathway | ↓# | SAEC | | [143] |