Abstract
Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16−/− mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16−/− mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.
Highlights
Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool
We hypothesized that p16 plays a role in the pathological processes associated with smoking and Chronic obstructive pulmonary disease (COPD), and that deletion of p16 protects the lung from the development of emphysematous-like tissue remodeling
COPD can be characterized as a disease of accelerated pulmonary aging
Summary
P16 expression is increased in human COPD lungs. To assess the expression and localization of p16 protein in human COPD/ emphysema, IHC was carried out on lung biopsies from agematched patients diagnosed with emphysema, normal nonsmokers, and normal (non-diseased) smokers. Senescence was assessed in alveolar type II cells (AECII) by double IHC staining of p16 and SPC. Increases of IL33 and TGFβ1 protein were observed in p16−/− mice; the protein levels (Fig. 3f) were not as elevated as those of p16+/+ CS These data suggest that p16 depletion prevents COPDassociated detrimental mediators from reaching pathological levels and leading to the structural and functional alterations associated with CS exposure. N, p16+/+ RA = 4–8, p16+/+ CS = 10–14, p16−/− RA = 4–7, and p16−/− CS = 12–14 mice p16 deletion reduces CS-induced senescence in AECIIs. In vivo cell proliferation was assessed by EdU incorporation. P16+/+ mice showed a threefold increase in p21 upon CS exposure compared with RA, strongly suggesting a role of senescence in CS-induced pulmonary dysfunction observed in p16+/+ mice. To further investigate the mechanism by which p16−/− mice are Static compliance (cmH2O/ml)
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