The role of Transient Receptor Potential (TRP) channels in the pathogenesis of COPD

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Title: The role of Transient Receptor Potential (TRP) channels in the pathogenesis of COPD
Author(s): Baxter, Matthew
Item Type: Thesis or dissertation
Abstract: COPD is currently the 4th most prevalent cause of death worldwide. Despite the global impact, there are no currently available treatments which impede disease progression. This lack of effective therapies is largely due to an inadequate understanding of the mechanisms which drive disease progression. Cigarette smoke (CS), the most important risk factor for COPD, is thought to initiate an inflammatory response in the lungs which becomes self-propagating and dysregulated. Chronically, this inflammatory response drives structural and functional changes. The mechanisms by which CS elicits this inflammatory response, however, remain unclear. Certain CS constituents are known to activate Transient Receptor Potential (TRP) ion channels. A number of TRP channels are actively expressed in the lung tissue or inflammatory cells, and a further few are also implicated in the generation of inflammation. Owing to these features, it was hypothesised that TRP channels A1, C6, M2, M8, V1 and V4 have a role in CS-induced airway inflammation and, consequently, the pathogenesis of COPD. To test this hypothesis, three murine models of induced airway inflammation were characterised: acute CS, sub-chronic CS and endotoxin (LPS). Lung-tissue TRP channel expression levels were measured in these models alongside human lung-parenchyma samples from non-smokers, smokers and emphysema patients. Mice deficient for specific TRP channels were profiled in the CS-model and the LPS-model to establish the role of TRP channels in the initiation of inflammation in disease and non-disease settings. TRPV1-/-, TRPV4-/- and TRPM8-/- mice exhibited significantly reduced levels of airway inflammation compared to wild-types after acute CS, but normal responses to the innate (LPS) challenge. This data suggests that modulation of TRP channels could represent a novel anti-inflammatory approach for combating smoke induced diseases like COPD without impacting on the normal, essential innate defence mechanisms.
Content Version: Open Access
Publication Date: Sep-2013
Date Awarded: Mar-2014
URI: http://hdl.handle.net/10044/1/29840
Advisor: Birrell, Mark
Belvisi, Maria
Sponsor/Funder: Medical Research Council (Great Britain)
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses



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