ORCID Profile
0000-0002-2073-5536
Current Organisation
Utrecht University
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Publisher: American Physiological Society
Date: 04-2023
DOI: 10.1152/AJPLUNG.00105.2022
Abstract: Lung fibroblasts are implicated in abnormal tissue repair in chronic obstructive pulmonary disease (COPD). The exact mechanisms are unknown and comprehensive analysis comparing COPD- and control fibroblasts is lacking. The aim of this study is to gain insight into the role of lung fibroblasts in COPD pathology using unbiased proteomic and transcriptomic analysis. Protein and RNA were isolated from cultured parenchymal lung fibroblasts of 17 patients with stage IV COPD and 16 non-COPD controls. Proteins were analyzed using LC-MS/MS and RNA through RNA sequencing. Differential protein and gene expression in COPD was assessed via linear regression, followed by pathway enrichment, correlation analysis, and immunohistological staining in lung tissue. Proteomic and transcriptomic data were compared to investigate the overlap and correlation between both levels of data. We identified 40 differentially expressed (DE) proteins and zero DE genes between COPD and control fibroblasts. The most significant DE proteins were HNRNPA2B1 and FHL1. Thirteen of the 40 proteins were previously associated with COPD, including FHL1 and GSTP1. Six of the 40 proteins were related to telomere maintenance pathways, and were positively correlated with the senescence marker LMNB1. No significant correlation between gene and protein expression was observed for the 40 proteins. We hereby describe 40 DE proteins in COPD fibroblasts including previously described COPD proteins (FHL1, GSTP1) and new COPD research targets like HNRNPA2B1. Lack of overlap and correlation between gene and protein data supports the use of unbiased proteomics analysis and indicates that different types of information are generated with both methods.
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2023
DOI: 10.1101/2023.08.02.551614
Abstract: 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. 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 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 . 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. 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. 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. 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.
Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2023
No related grants have been discovered for Nicolaas Bekker.