- Title
- Investigating new treatments for chronic obstructive pulmonary disease
- Creator
- Vinod Kumar,
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Chronic obstructive pulmonary (COPD) disease is a highly destructive lung disease with high personal and social burden. Cigarette smoke is the predominant risk factor for the development of COPD, with 50% of lifelong smokers developing this disease during their lifetime. COPD is continuing to increase in prevalence and is now ranked as the 3rd leading cause of death worldwide. This results from a lack of an effective treatment, which in turn is largely due to the poor understanding of the mechanisms of disease pathogenesis. The pathogenesis of COPD is characterized by inflammation of bronchi, lung fibrosis and alveolar destruction. COPD is progressive in nature, and the lung destruction is not fully reversible. Oxidative stress and abnormal inflammatory responses have been implicated in the pathogenesis of COPD. Additionally, endogenous antioxidant and anti-inflammatory factors which are crucial in maintaining lung homeostasis are depleted in COPD patients. Consequently, understanding the mechanisms of disease pathogenesis is crucial for the development of potential therapeutic interventions and disease management. This thesis describes a series of studies that I performed to understand the causes and mechanisms of oxidative stress and inflammation that drive COPD pathogenesis and target them with novel antioxidant and anti-inflammatory molecules as potential treatments. I utilised a short-term cigarette smoke-induced experimental murine model that our group developed and have used extensively, which recapitulates the hallmark features of human COPD. I showed that cigarette smoke exposure had significant impact in altering the levels of endogenous hydrogen sulfide (H2S), which is an antioxidant and anti-inflammatory molecule and maintains lung homeostasis. H2S deficiency was found to be associated with mitochondrial dysfunction-induced oxidative stress and inflammation, which are key drivers of COPD pathogenesis. Over-expressing mitochondrial catalase (MCAT), an endogenous antioxidant enzyme, significantly attenuated oxidative stress and prevented the development of hallmark features of COPD in mice. Similarly, supplementing H2S specifically in mitochondria with mitochondria-targeted hydrogen sulfide donors (mtH2SDs), prevented cigarette smoke-induced inflammation, hallmark features of COPD, mitochondrial dysfunction and oxidative stress. Furthermore, I showed that supplementing H2S in mitochondria reverses pre-existing lung damage induced by cigarette smoke exposure in mice. Using our experimental model, I also demonstrated the involvement of the lung vascular endothelium, which plays a crucial role in immune cell infiltration from the circulation into the lungs. I showed that cigarette smoke exposure alters the expression dynamics of cells adhesion molecules on endothelial cells, which was partially normalised by treatment with mtH2SDs in mice. I further profiled lung immune cells, and showed altered populations of monocytes, neutrophils and alveolar and interstitial macrophages following cigarette smoke exposure, and mtH2SDs treatment had a significant impact in preventing these alterations. I further advanced my research by studying lung macrophage phenotype and polarization in experimental COPD. I found altered macrophage phenotype and polarization of alveolar and interstitial macrophages in the lungs in experimental COPD. However, the treatment with mtH2SDs did not prevent these alterations induced by cigarette smoke exposure. To translate the findings from experimental COPD to human, I tested the effects of mtH2SDs in human primary bronchial epithelial cells derived from healthy individuals and COPD patients and exposed to cigarette smoke extract (CSE). I showed that treatment with mtH2SDs prevented CSE-induced oxidative stress and partially suppressed inflammation by mitigating the release of pro-inflammatory mediator interleukin (IL)-8. These findings have advanced our understanding of the mechanisms of oxidative stress and altered immune responses in COPD pathogenesis. They have also highlighted a significant role of endogenous MCAT and H2S in maintaining lung homeostasis and preventing the development of COPD. Finally, my findings have demonstrated a new effective therapeutic strategy, and may potentially be developed into mitochondria-targeted interventions to treat COPD and related lung diseases.
- Subject
- COPD; inflammation; oxidative stress; mitochondria-targeted interventions
- Identifier
- http://hdl.handle.net/1959.13/1504643
- Identifier
- uon:55559
- Rights
- Copyright 2022 Vinod Kumar
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 4 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 351 KB | Adobe Acrobat PDF | View Details Download |