Therapeutic targeting of mitochondrial dysfunction in chronic obstructive pulmonary disease (COPD)

Das, Shatarupa

Therapeutic targeting of mitochondrial dysfunction in chronic obstructive pulmonary disease (COPD)

Das, Shatarupa

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Publication Type:: Thesis
Issue Date:: 2022

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Field	Value	Language
dc.contributor.author	Das, Shatarupa
dc.date.accessioned	2023-10-16T02:09:20Z
dc.date.available	2023-10-16T02:09:20Z
dc.date.issued	2022
dc.identifier.uri	http://hdl.handle.net/10453/172683
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Chronic obstructive pulmonary disease (COPD) is characterised by airway inflammation resulting in irreversible damage to the lung, which leads to alveolar destruction (emphysema), and impaired lung function. Currently, there are no available treatments that inhibit the progression or reverse the disease. Cigarette smoking (CS) is one of the predominant causes of COPD and is an instigator of inflammation in the lung via oxidative stress which induces the over-activation of PARP-1. PARP-1 is a major consumer of NAD+, a critical energy intermediate for mitochondrial function. Currently, there is limited knowledge as to how NAD+ metabolism is altered in COPD and whether targeting NAD+ pathways can have therapeutic benefits in COPD. We examined the efficacy of NAD+ targeted therapeutics, NR and PT in COPD. In our COPD mouse model, we found reduced NAD+ levels associated with PARP hyperactivity in the lung. We also observed an increase in oxidative stress and inflammatory markers. Based on these findings, we hypothesised that reduced NAD+ levels may increase oxidative stress and inflammation in COPD. Thus, we investigated the therapeutic effect of NR and PT in halting the progression and reversing the disease features. Following daily dietary administration of NR and PT both prophylactically and therapeutically, we found significant reductions in inflammation, emphysema, and improved lung function. NR and PT also restored NAD+ levels and PARP activity in COPD, resulting in reduced oxidative stress. COPD exacerbations are driven by chronic inflammation, however, the exact metabolic interactions in the immune cells involved during the progression of the disease remain unknown. Therefore, another objective of this study was to understand how chronic exposure to CS leads to impaired metabolism in COPD. Using our COPD mouse model, we determined that chronic CS exposure results in reduced PKM1, PKM2, HIF1α and PGC1α levels indicating reduced metabolism in the lung, we also observed an increase in oxidative stress and inflammatory markers. Based on these findings, we hypothesised that PKM2 imbalances may be an important driver of immunometabolism and oxidative stress in COPD. We then investigated the therapeutic efficacy of TEPP46, an activator of PKM2 in COPD mouse model. Following daily administration, we found that TEPP46 significantly reduced inflammation, emphysema, and improved lung function measurements. Critically, TEPP46 also restored PKM2 and HIFα imbalances and promoted metabolic function, resulting in reduced oxidative stress. In conclusion, NR, PT and TEPP46 reduced COPD features in COPD mouse studies and have significant potential as therapeutics for COPD.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/172683/2/02whole.pdf
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.rights	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.
dc.rights	© 2022 Shatarupa Das
dc.rights	au.edu.uts.lib/nph
dc.title	Therapeutic targeting of mitochondrial dysfunction in chronic obstructive pulmonary disease (COPD)	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	embargoed	*
utslib.copyright.embargo	2024-12-31T00:00:00+1000

Abstract:

Chronic obstructive pulmonary disease (COPD) is characterised by airway inflammation resulting in irreversible damage to the lung, which leads to alveolar destruction (emphysema), and impaired lung function. Currently, there are no available treatments that inhibit the progression or reverse the disease. Cigarette smoking (CS) is one of the predominant causes of COPD and is an instigator of inflammation in the lung via oxidative stress which induces the over-activation of PARP-1. PARP-1 is a major consumer of NAD+, a critical energy intermediate for mitochondrial function. Currently, there is limited knowledge as to how NAD+ metabolism is altered in COPD and whether targeting NAD+ pathways can have therapeutic benefits in COPD. We examined the efficacy of NAD+ targeted therapeutics, NR and PT in COPD. In our COPD mouse model, we found reduced NAD+ levels associated with PARP hyperactivity in the lung. We also observed an increase in oxidative stress and inflammatory markers. Based on these findings, we hypothesised that reduced NAD+ levels may increase oxidative stress and inflammation in COPD. Thus, we investigated the therapeutic effect of NR and PT in halting the progression and reversing the disease features. Following daily dietary administration of NR and PT both prophylactically and therapeutically, we found significant reductions in inflammation, emphysema, and improved lung function. NR and PT also restored NAD+ levels and PARP activity in COPD, resulting in reduced oxidative stress. COPD exacerbations are driven by chronic inflammation, however, the exact metabolic interactions in the immune cells involved during the progression of the disease remain unknown. Therefore, another objective of this study was to understand how chronic exposure to CS leads to impaired metabolism in COPD. Using our COPD mouse model, we determined that chronic CS exposure results in reduced PKM1, PKM2, HIF1α and PGC1α levels indicating reduced metabolism in the lung, we also observed an increase in oxidative stress and inflammatory markers. Based on these findings, we hypothesised that PKM2 imbalances may be an important driver of immunometabolism and oxidative stress in COPD. We then investigated the therapeutic efficacy of TEPP46, an activator of PKM2 in COPD mouse model. Following daily administration, we found that TEPP46 significantly reduced inflammation, emphysema, and improved lung function measurements. Critically, TEPP46 also restored PKM2 and HIFα imbalances and promoted metabolic function, resulting in reduced oxidative stress. In conclusion, NR, PT and TEPP46 reduced COPD features in COPD mouse studies and have significant potential as therapeutics for COPD.

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http://hdl.handle.net/10453/172683