Introduction and Objectives Accelerated lung ageing has been implicated in the pathogenesis of COPD and therefore targeting cellular senescence may have therapeutic benefit. COPD is increasingly felt to have significant sub-phenotypes with large and small airway involvement. The airway epithelium likely endures the majority of potentially senescence-inducing insults. However, data on airway epithelial cell (AEC) senescence in COPD is limited and comparisons between large and small airways are lacking. Furthermore, the role of infection in COPD-associated senescence is unclear. To date, senescence in bronchiectasis has not been investigated as a model for infection-induced senescence. We sought to determine AEC expression of senescence-associated markers in COPD and bronchiectasis and to compare large and small airways.

Methods Lung explant tissue from our transplant programme from COPD (n = 19) and bronchiectasis (n = 14) with resection tissue from smokers without lung disease (control) (n = 11) was stained for senescence-associated markers by immunohistochemistry. Staining was quantified semi-quantitatively. Fluorescence in situ hybridisation (FISH) was used to investigate telomere length and possible co-localisation with DNA damage-associated proteins.

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Abstract S65 Figure 1.

Expression of Ki67 (A), SIRT1 (B), p16 (C) and γH2AX (D) in large AECs and small AECs (E, F, G and H, respectively). Results are expressed as mean ± SEM. Statistics: Kruskal-Wallis and Mann-Whitney U test. * p < 0.05, ** p < 0.01, *** p < 0.001.

Results In large AECs, expression of the proliferation marker ki67 and the anti-ageing protein sirtuin 1 (SIRT1) was decreased in COPD as compared to bronchiectasis and controls. There was no difference in expression of the cell-cycle inhibitor p16 and the DNA damage associated foci ?H2AX between the three groups. In small AECs, SIRT1 was decreased in COPD compared to controls and p16 and ?H2AX were increased. Here, ki67 expression did not differ between groups. In bronchiectasis, there was no significant change in senescence marker expression compared to controls, with the exception of decreased SIRT1 in large AECs. Marker expression was not significantly correlated with FEV₁ or smoking history. Preliminary work suggests potential co-localisation of ?H2AX at telomeres with ongoing analysis underway.

Conclusions Differential expression of senescence-associated markers between large and small airways in COPD may reflect the distinct patterns of inflammation and functional impairment occurring in the two airway compartments. There is some evidence suggesting a role for senescence in bronchiectasis, though this is less clear than for COPD. Further markers need to be investigated.