LAUSR

Background: Progressive small airway fibrosis is a key feature of early COPD. In COPD, cellular senescence levels are increased and may relate to disease progression. Peripheral parenchymal fibroblasts are pro-inflammatory and dysfunctional in COPD, but the role of small airway fibroblasts (SAF) and the impact of senescence are unknown. Aim: Compare senescence and pro-fibrotic markers of SAF from COPD patients to age-matched controls. Method: SAF were isolated from non-smoker and COPD surgical lung resections. Gene expression was measured by qPCR, protease activity by zymography, cell proliferation using iCELLigence impedance and senescence cells by senescence-associated β-galactosidase (SA-βGal) staining, p16INK4a and p21Waf1 expression. Results: COPD SAF displayed reduced proliferation (n=4-5, Fig. 1), increased SA-βGal staining (n=6), and elevated p21 (34%) and p16 (12%) expression compared to control non-smoker SAF. Whilst gene expression of MMP2/9 was unchanged (n=3-7), pro-MMP2 was significantly increased (102%, p=0.02) in COPD SAF and similarly trends in elevated pro- and active-MMP2/9 (15-28%). COPD SAF also displayed trends in increased αSMA (25%), COL1A1 (40%) and COL3A1 (20%, n=5) expression. Conclusion: This suggests COPD SAF show cellular senescence, have elevated MMPs and pro-fibrotic markers compared to non-smoker. Elucidating the mechanism underlying this phenotype could lead to future targets of airway fibrosis and COPD.