Investigating the role of TRPA1 and TRPV1 ion channels in the cough reflex
Author(s)
Grace, Megan Stacey
Type
Thesis
Abstract
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.
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.
Date Issued
2011
Date Awarded
2012-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Belvisi, Maria
Birrell, Mark
Sponsor
Medical Research Council (Great Britain) ; Wellcome Trust (London, England)
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)