Cellular Senescence Affects ECM Regulation in COPD Lung Tissue

Higher levels of cellular senescence have been demonstrated in COPD patients, including severe early onset (SEO)-COPD. Recently we demonstrated a link between senescence and extracellular matrix (ECM) changes in lung fibroblasts. Whether this in vitro observation also translates in vivo has not been demonstrated yet. Therefore, we aimed to determine whether senescence can contribute to COPD-associated ECM-related changes in lung tissue. Transcriptomics and proteomics analyses were performed on lung tissue from 60 COPD patients (including 18 SEO-COPD patients) and 32 controls. Transcript and protein levels of 471 ECM-related proteins were compared between (SEO-)COPD and control. Differentially expressed genes and proteins were correlated with six major senescence markers. Significant correlations were validated at single cell level and in vitro. We identified 15 COPD- and 61 SEO-COPD-associated changes in ECM-related proteins, of which 12 and 57 at transcript and 4 and 9 at protein level, respectively. More than half (36 out of 68) of the (SEO-)COPD-associated ECM-related genes/proteins were significantly correlated with one or more senescence markers at transcript level, with the most and strongest correlations with p21. The correlation of 6 ECM-related genes, including THBS1, ADAMTS1, and ADAMTS4, with p21 was validated at single cell level. Many of the (SEO-)COPD-associated ECM-related changes in lung tissue were correlated with the senescence marker p21. As many of these ECM-related proteins are involved in ECM organization and include proteases, these results indicate a role for cellular senescence in disturbed ECM organization and the protease-antiprotease imbalance in COPD.