Higher levels of cellular senescence have been demonstrated in COPD-derived lung tissue and lung fibroblasts. Previously, we found a link between senescence and extracellular matrix (ECM) dysregulation in COPD, including lower decorin expression and secretion with higher levels of senescence in COPD. Targeting senescent fibroblasts with senolytics may be a promising strategy to restore normal ECM regulation in COPD. The aim of this project was to elucidate whether treating senescent primary lung fibroblasts with senolytics can restore COPD-associated ECM changes in lung fibroblasts.

Senescent parenchymal lung fibroblasts (n=10) were treated with 5 different senolytic drugs in a model of PQ-induced senescence. The senolytic effect was assessed by measuring apoptosis levels (Annexin V) and the senescence marker SA-?-gal. The restore of senescence-induced ECM changes was assessed by measuring decorin secretion with ELISA.

The senolytics Navitoclax, A-1155463 and Venetoclax significantly induced apoptosis specifically in PQ-induced senescent fibroblasts (2.4-, 5.0 & 3.7-fold resp.) compared to naïve fibroblasts and reduced the number of SA-?-gal positive cells (7%, 6% & 10% resp.). Dasatinib and Quercetin did not have senolytic effects neither in combination, nor separately. The PQ-induced decrease in decorin secretion was partly restored and significantly increased by A-1155463 and Venetoclax (2.6- & 1.5-fold resp.).

The senolytics Navitoclax, A-1155463 and Venetoclax were effective in reducing cellular senescence in primary lung fibroblasts. Importantly, A-1155463 and Venetoclax increased decorin secretion in senescent lung fibroblasts, showing the potential to restore senescence-induced ECM dysregulation in COPD.