Regulation of cellular senescence in COPD small airway fibroblasts
File(s)
Author(s)
Wrench, Catherine Louise
Type
Thesis
Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung condition associated with small airway obstruction due to fibrosis and airway collapse (small airways disease (SAD)). COPD is associated with cellular senescence; by which cells undergo irreversible growth arrest and can be induced by stressors such as oxidative stress. Senescent cells are not inert but remain metabolically active expressing the senescence-associated secretory phenotype (SASP), that induces inflammation and tissue remodelling. Fibroblasts deposit extracellular matrix (ECM) and may facilitate SAD. Senescence is associated with a pro-fibrotic fibroblast phenotype in fibrotic lung disease, however only parenchymal-derived fibroblasts have been studied in this context in COPD. Whether small airway-derived fibroblasts (SAF) are senescent in COPD and how this contributes to SAD is largely unknown.
SAF from age-matched non-smokers, smokers and COPD patients were examined for their senescent and fibrotic characteristics, and whether oxidative stress induces this phenotype. To better understand the pathways involved in driving senescence and if this is linked to a fibrotic phenotype, a senescent-enriched population of COPD SAF was isolated using fluorescence-activated cell sorting (FACS) and studied further.
Markers of senescence were increased in COPD SAF compared to non-smoker SAF. These included SASP mediators that can promote fibrosis. COPD SAF trended towards depositing more collagen type III compared to non-smoker SAF. Oxidative stress-induced cellular senescence and pro-fibrotic mediator expression but did not elevate ECM expression in this model. Using FACS, a senescence-enriched population of SAF was isolated, as determined by senescence marker expression and displayed increased ECM markers expression and a SASP that may influence fibrosis.
This study suggests COPD SAF are senescent and possibly associated with fibrotic properties. Oxidative stress can mediate this senescent phenotype but needs further exploration for its contribution to fibrosis. Targeting of cellular senescence in SAF may limit fibrosis and therefore the progression of SAD.
SAF from age-matched non-smokers, smokers and COPD patients were examined for their senescent and fibrotic characteristics, and whether oxidative stress induces this phenotype. To better understand the pathways involved in driving senescence and if this is linked to a fibrotic phenotype, a senescent-enriched population of COPD SAF was isolated using fluorescence-activated cell sorting (FACS) and studied further.
Markers of senescence were increased in COPD SAF compared to non-smoker SAF. These included SASP mediators that can promote fibrosis. COPD SAF trended towards depositing more collagen type III compared to non-smoker SAF. Oxidative stress-induced cellular senescence and pro-fibrotic mediator expression but did not elevate ECM expression in this model. Using FACS, a senescence-enriched population of SAF was isolated, as determined by senescence marker expression and displayed increased ECM markers expression and a SASP that may influence fibrosis.
This study suggests COPD SAF are senescent and possibly associated with fibrotic properties. Oxidative stress can mediate this senescent phenotype but needs further exploration for its contribution to fibrosis. Targeting of cellular senescence in SAF may limit fibrosis and therefore the progression of SAD.
Version
Open Access
Date Issued
2019-12
Date Awarded
2020-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Barnes, Peter
Donnelly, Louise
Sponsor
NHLI Studentship
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)