The role of accelerated ageing in aberrant lung tissue repair and remodelling in COPD

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, while the prevalence is still increasing. Since the exact COPD pathogenesis is still unknown and no effective therapeutics are available to stop the progression of the disease, novel insights into the pathogenesis of COPD are urgently needed. Accelerated ageing has been postulated to play a role in COPD with characteristic of ageing demonstrated in lungs from COPD patients compared to age-matched smokers without COPD. Recently, extracellular matrix (ECM) dysregulation has been described as an additional ageing hallmark of the lungs. ECM dysregulation can cause aberrant lung tissue repair and remodelling. Lung fibroblasts and airway smooth muscle cells (ASMCs) are the major producers and regulators of the ECM and therefore play an important role in lung tissue repair and remodelling. The aim of this thesis was to elucidate the role of accelerated ageing in aberrant tissue repair and remodelling in COPD. We analysed ageing markers and ECM changes in lung fibroblasts and ASMCs from COPD patients compared to ex-smoker controls without COPD matched for age, gender, and smoking history. In addition, we assessed the functional effects of induction of cellular senescence, which is a major ageing hallmark. We found characteristics of accelerated ageing in COPD-derived fibroblasts compared to lung fibroblasts from matched controls, including higher levels of cellular senescence. The increase in cellular senescence in COPD-derived fibroblasts was associated with lower levels of the ECM protein decorin and higher levels of pro-inflammatory protein secretion. Induction of cellular senescence in lung fibroblasts also resulted in ECM changes, secretion of pro-inflammatory proteins and impaired tissue repair functions of the fibroblasts. Furthermore, ASMCs had higher levels of cellular senescence compared to lung fibroblasts from the same patients, but in ASMCs no differences were found between COPD and control. Finally, we showed that E-cigarette extract induces cellular senescence in lung fibroblasts, and the induction in cellular senescence resulted in impaired tissue repair functions. Therefore, we concluded that E-cigarettes, commonly used as smoking alternative or as smoke cessation aid, are not a safe alternative for tobacco smoking. These studies indicate that accelerated ageing plays a role in aberrant tissue repair and remodelling in COPD and thereby contributes to the pathogenesis of COPD. Future studies should unravel the exact mechanisms that lead to accelerated ageing in COPD to discover therapeutics targets to develop therapies that target accelerated ageing in COPD patients.

Author dc:creator

• Woldhuis, Roy Rolf

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• The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
• au.edu.uts.lib/ppc
• info:eu-repo/semantics/openAccess

Language dc:language.iso

en_US

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http://hdl.handle.net/10453/154792

OAI identifier oai:identifier

oai:opus.lib.uts.edu.au:10453/154792