Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/928201
- Title
- Understanding the inflammatory mechanisms that predispose to emphysema in mouse models
- Author/Creator
-
Lam, Chuan En Eric
- Institution
- University of Newcastle. Health, Biomedical Science and Pharmacy
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Chronic obstructive pulmonary disease (COPD) is a growing global health problem, and this disorder is projected to rank fifth by 2020 as a worldwide burden of disease (Murray and Lopez., 1996). Remarkably, little is known about the pathogenesis of COPD and current pharmacologic agents fail to halt disease progression. Emphysema is a major inflammatory disorder that falls under the clinical description of COPD. Emphysema can be induced by smoking but can also occur in non-smokers. Emerging data suggests that the loss of alveolar tissue which characterises emphysema may result from increased cell death (apoptosis) of alveolar epithelial cells mediated by the sphingolipid mediator ceramide (Petrache et al., 2005). The cause of COPD exacerbations are commonly bacterial or viral respiratory infections. Under certain conditions, immunity from infection is mediated through the initiation of apoptotic pathways by infected cells to prevent the pathogen from replicating within the host. Toll-like receptors (TLRs) recognise molecular patterns expressed by pathogens such as bacteria and viruses to initiate innate immune responses. Notably, significant amounts of the bacterial wall component lipopolysaccharide (LPS) are found in cigarette smoke. LPS is a TLR4 ligand that increases the level of the apoptotic mediator ceramide and production of proinflammatory cytokines (such as tumour necrosis factor (TNF)–α, interleukin (IL)-1β, and IL-6) implicated in the pathogenesis of emphysema. We hypothesise that chronic inhalation of LPS leads to the dysregulation of TLR4 signalling pathways that increases susceptibility to respiratory infection, and uncontrolled inflammation that promotes alveolar cell apoptosis and emphysematous-like lesions. We developed mouse models of LPS- and bacterial-induced emphysema to determine if attenuating inflammation can prevent the development of emphysema. Our results demonstrate that exposure to LPS or infection with Non-typeable Haemophilus influenzae (NTHi) (often found in patients with emphysema) can induce hallmark features of emphysema, such as alveolar enlargement (determined by mean linear intercept and percentage alveolar airspace measurements) and inflammation dominated by neutrophils and macrophages. We demonstrated that alveolar enlargement was due to the loss of alveolar parenchyma (from apoptosis), is dependent on TLR4 and myeloid differentiation factor-88 (MyD88), increased proinflammatory cytokines, chemokines, and inflammatory cells (neutrophils and macrophages) in the lung. Prophylactic administration of synthesised chemerin-derived peptide (C15) attenuated LPS- or NTHi-induced inflammation, which resulted in inhibition of the development of emphysematous-like lesions. Notably, specific depletion of alveolar macrophages protects mice from LPS- or NTHi-induced emphysema. Collectively, we demonstrate that blocking inflammation during the development of emphysema is critical for preventing or attenuating the progression of the disease.
- Relation
- University of Newcastle Research Higher Degree Thesis
- Date
- 2011
- Keyword(s)
-
emphysema;
COPD;
apoptosis;
chemerin
- Resource Type
- thesis
- Rights
- Copyright 2011 Chuan En Eric Lam
- Identifier
- http://hdl.handle.net/1959.13/928201
- Language
- eng
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-
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