Cellular Senescence Affects ECM Regulation in COPD Lung Tissue

Rationale Higher levels of 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. Objectives To determine whether senescence can contribute to COPD-associated ECM-related changes in lung tissue. Methods 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 . Results 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 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 and ADAMTS1 in senescent lung fibroblasts in vitro . Conclusions 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 protease-antiprotease imbalance in COPD. What is already known on this topic Accelerated ageing, including cellular senescence, has been recognized as a feature of COPD, while the functional implications of higher levels of senescence on lung tissue are largely unclear. Previously, we demonstrated a link between senescence and extracellular matrix (ECM) dysregulation in primary lung fibroblasts, but whether this translates in vivo has not been demonstrated yet. What this study adds Here, we demonstrate that cellular senescence is linked to ECM dysregulation in vivo in COPD lung tissue mainly by impacting the regulators of ECM organization and contributing to the protease-antiprotease imbalance in COPD. How this study might affect research, practice or policy Our study points towards an important functional consequence of increased senescence on disease pathology in COPD patients, including the protease-antiprotease imbalance and dysregulated elastogenesis. Our findings support the development of new therapeutic strategies of targeting senescence to restore ECM regulation in COPD. ### Competing Interest Statement Prof. Timens reports incidental consulting fees from Merck Sharp Dohme, Bristol-Myers-Squibb, and Altana, outside the submitted work. Prof. Timens reports to be board member of Dutch Society of Pathology and member of Council for Research and Innovation of the Federation of Medical Specialists, outside the submitted work. All other authors have nothing to disclose.