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Title: Investigating the role of TRPA1 and TRPV1 ion channels in the cough reflex
Author: Grace, Megan Stacey
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Cough is under the control of sensory afferents which innervate the airways via the vagus nerve. Cough is an important protective reflex that clears the airway, but can become exacerbated and deleterious when associated with airways diseases, in which there is enhanced release of inflammatory mediators and a decrease in lung pH. These mediators sensitise airway afferents and could be driving enhanced cough associated with inflammation. Transient Receptor Potential (TRP) ion channels are associated with several disease pathologies. TRPV1 has an established role in cough, and is implicated in the aetiology of chronic cough; and TRPA1 is a promising new target. Involvement of these ion channels in the tussive reflex is awaiting comprehensive investigation. I have therefore explored the role of TRPA1 and TRPV1 in tussive responses to the endogenous irritants prostaglandin E2 (PGE2), bradykinin (BK) and low pH. To do this I have used selective antagonists and genetically modified mice in models of human, guinea pig and mouse vagal sensory nerve depolarisation; conscious guinea pig cough; and guinea pig primary ganglia cell imaging. TRPA1 and TRPV1 were shown to mediate PGE2 and BK-induced nerve depolarisation, cough, and activation of ganglia cells. In contrast, low pH-induced nerve depolarisation and ganglia cell activation was mediated via TRPV1 or Acid Sensing Ion Channels (ASICs); whereas, cough was partially attenuated with TRPA1 or TRPV1 antagonists. In summary, I have identified that TRPA1 and TRPV1 mediate PGE2 and BK-induced cough; and provided evidence that low pH-induced sensory nerve activation is mediated via TRPV1 and ASICs, but a role for TRPA1 is still unclear. These are exciting findings which add to our understanding of the mechanisms that drive the cough reflex in the healthy state; builds a base for investigating cough hypersensitivity in disease; and could help to guide the development of novel efficacious anti-tussive therapies.
Supervisor: Belvisi, Maria ; Birrell, Mark Sponsor: Medical Research Council ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available