Cellular Senescence Affects ECM Regulation in COPD Lung Tissue

Abstract

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) dysregulation in lung fibroblasts. Whether this in vitro observation also translates in vivo has not been shown yet. 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. Expression levels of 471 ECM-related genes and proteins were compared between (SEO-)COPD and controls. Differentially expressed ECM-related genes and proteins were then correlated with six major senescence markers. ECM-senescence correlations were validated in primary human lung fibroblasts in vitro. Results: We identified 12 COPD- and 57 SEO-COPD-associated ECM-related genes and 4 COPD- and 9 SEO-COPD-associated ECM-related proteins. More than half (36 out of 68 unique genes) 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 (26 genes). The correlation of 3 ECM-related genes with p21 was validated in primary lung fibroblasts cultured at baseline and ADAMTS1 was increased in senescence-induced lung fibroblasts. 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.