- Title
- Investigation of pathogenesis of chronic obstructive pulmonary disease
- Creator
- Haw, Tatt Jhong
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Chronic Obstructive Pulmonary Disease (COPD) affects more than 64 million people globally and is primarily caused by cigarette smoke (CS) exposure. It is the third leading cause of morbidity and mortality worldwide and imposes significant socioeconomic burden worldwide. COPD is a chronic lung disease characterised by chronic pulmonary inflammation, airway remodelling and emphysema. These pathologies consequently culminate in progressive lung function decline and airflow limitation. Current therapies for the management of COPD are largely ineffective. They provided symptomatic relief to patients and do not target the underlying causal factors of COPD. Hence, there is a lack of effective treatments and an urgent need for research into the identification and development of therapeutic strategies in treating COPD. The lack of effective treatments is due to the poor understanding of immunological processes and mechanisms that underpin the pathogenesis of COPD. Our laboratory has recently established a murine experimental model of COPD by exposing mice to nose-only inhalation of tightly regulated dose of CS. Importantly, our CS-induced model of COPD recapitulates the hallmark features of human disease in a relatively short period of time. Thus, this allows us to investigate and examine the immunological processes and mechanisms that underpin the pathogenesis of COPD. The aims of the studies described in this thesis were to identify and elucidate immunological processes that underpin the pathogenesis of COPD. The first study identified a novel role for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting CS-induced COPD. TRAIL and its receptors were increased by CS exposure in mice and in lung samples from human COPD patients. TRAIL-deficient mice or wild-type (WT) mice treated with neutralising TRAIL monoclonal antibodies had significantly reduced CS-induced pulmonary inflammation, expression of pro-inflammatory mediators, emphysema-like alveolar enlargement and improved lung function. The second study investigated the role of Toll-like receptor (TLR)2 and TLR4 in CS-induced pathogenesis of COPD. CS-induced pulmonary inflammation was largely unaltered in the absence of TLR2 or TLR4. TLR2-deficient mice had CS-induced emphysema-like alveolar enlargement, apoptosis and impaired lung function compared to normal air-exposed mice that was equivalent to CS-exposed WT mice, whilst small airway remodelling was not altered. By contrast, TLR4-deficient mice had reduced CS-induced emphysema-like alveolar enlargement, apoptosis and impaired lung function compared to WT mice. Interestingly, CS-induced small airway fibrosis, characterised by increased collagen deposition around small airways, was ablated in TLR4-deficient mice. The third study identified a previously unrecognised role for TLR7 in the pathogenesis of COPD. In the absence of TLR7, CS-induced pulmonary inflammation was not altered compared to CS-exposed WT controls. CS-induced small airway epithelial cell thickening was reduced whilst collagen deposition increased in the absence of TLR7. Importantly, CS-induced emphysema-like alveolar enlargement and apoptosis were reduced in TLR7-deficient mice. Administration of the TLR7 agonist imiquimod synergistically increased CS-induced emphysema and apoptosis. Interestingly, imiquimod-induced emphysema and apoptosis may occur through the activity of mast cell-specific proteases, in particular mouse mast cell protease-6 (mMCP-6). Crucially, antibody-mediated neutralisation of TLR7 also reduced CS-induced emphysema and apoptosis in the lungs in experimental COPD. Our novel findings indicate that TRAIL and TLRs, in particularly TLR2, TLR4 and TLR7, have critical roles in CS-induced development of COPD. TRAIL promotes CS-induced pulmonary inflammation, emphysema-alveolar enlargement and lung function impairment. TLRs have little or minor role in CS-induced pulmonary inflammation. TLR2 may protect against CS-induced emphysema and lung function impairment, whilst TLR4 and TLR7 induce these disease features of COPD. TLR4 promotes CS-induced airway fibrosis whilst TLR2 and TLR7 regulate collagen deposition around small airways. Collectively, our studies significantly advance the understanding of the immunological mechanisms that underpin the pathogenesis of COPD and may facilitate the development of novel treatments for COPD in the future.
- Subject
- chronic obstructive pulmonary disease; cigarette smoke; TRAIL; TLR2; TLR4; TLR7; pulmonary inflammation; airway remodelling; emphysema; lung function
- Identifier
- http://hdl.handle.net/1959.13/1318484
- Identifier
- uon:23630
- Rights
- Copyright 2016 Tatt Jhong Haw
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 15 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 345 KB | Adobe Acrobat PDF | View Details Download |