An Investigation Into the Mechanism of Inhalation Cough Challenge
Condition: Cough
MeSH terms: Cough
Study type: Interventional

Summary: 
      Despite its commonplace use in respiratory medicine the mechanism whereby inhalation
      challenge with a variety of mild acid aerosols produces a dose related and predictable cough
      is unknown. In this proposal the investigators wish to use established cough challenge
      methodology to explore the mechanism of action of agents provoking cough both in health and
      disease.

      The hypotheses to be tested include:

        -  Intracellular changes in pH, rather than extracellular changes, are key in the
           activation of TRP receptors, the main sensor for provoking cough.

        -  ATP acting through P2X channels is the mechanism of increased nerve excitability
           underlying cough hypersensitivity.
    

Detailed description: 
      The investigators have previously demonstrated that mild acids, such as citric, tartaric or
      phosphoric acid produce a highly reliable cough challenge and that the sensitivity of these
      are complex individual acids correlates within the population studied inferring a common
      mechanism of action.In contrast there is no correlation with the other common cough challenge
      methodology, capsaicin inferring that there are at least two different mechanisms for
      producing cough with aerosols in man.

      Over the past 10 years it has been established that capsaicin works by a specific irritant
      receptor known as the TRPV1. A second receptor, TRPA1 has been recently discovered and we
      were the first group to demonstrate that inhalation of agonists of this receptor in the form
      of the extract of cinnamon (cinnamaldehyde) produces cough in man . TRPA1 is a very
      attractive candidate for the main cough receptor since it is activated by many common
      irritants, such as smoke, perfumes and other strong smells known to provoke coughing in
      patients.

      The investigators have cloned the human TRP receptors and expressed them in cell lines. This
      in vitro work has allowed us to investigate the molecular action of the TRP receptors.
      Recently, the investigators and others have shown that weak acids can activate TRPA1, not as
      previously thought by stimulating the external surface of the cells but by altering the
      intracellular pH. This would explain why weak and not strong acids are better at producing
      cough, since weaker acids (technically those with a higher pKa) exist in solution in a form
      which is able to cross the cell membrane and render a change in the intracellular pH, which
      in turn activates TRPA1 from inside the cell.

      In the first study the investigators wish to the simply alter the pH of the nebulised
      solution provoking cough by altering the balance of the salts in the solution, and then carry
      out standard cough challenge protocols.

      In a second study the investigators wish to examine the effect of a number of known agonists
      of TRPA1 which are commonly used in the perfumes and foodstuffs in order to understand the
      rank order of potency of these compounds as tussive agents. This can then be compared to the
      rank order of potency of the same compounds in causing intracellular pH change in in vitro
      cell culture systems, in order to test the strength of the hypothesis over a variety of
      different agonists.

      Finally, recent work has shown that blockade of a neuronal ion channel known as P2X3 can
      dramatically reduce cough. P2X3 responds to the substance adenosine triphosphate (ATP), which
      has previously been used as a cough challenge solution in man. If the hypothesis that the
      cough hypersensitivity seen in patients is due to activation of P2X3 is correct then patients
      will cough at much lower doses of ATP than normal volunteers. We wish to assess the value of
      ATP, and the related substance AMP and adenosine in a cough challenge protocol. Studying the
      cough produced by these naturally occurring compounds may allow us to distinguish patients
      with cough hypersensitivity from those with cough due to other causes, and also lead to a
      methodology important in future drug development

      The greater understanding of the cough reflex which these studies would yield would have
      important clinical applications pointing the way to novel therapeutic avenues, as well as
      enhancing our fundamental understanding of the genesis of cough.
    

Intervention name(s): Nebulised citric acid in serial dilutions; Nebulised ATP solution in serial dilutions; Nebulised TRPA1 agonist solution in serial dilutions
Intervention type(s): Other; Other; Other
Intervention description(s): Citric acid will be delivered in serial dilutions as per the clinical trials unit standard operating procedure for cough challenge using KoKo Digidoser, based on ERS guidelines. Challenge will be repeated until C5 (5 coughs in 30 seconds following challenge) is elicited.; ATP solution will be delivered in serial dilutions as per the clinical trials unit standard operating procedure for cough challenge using KoKo Digidoser, based on ERS guidelines. Challenge will be repeated until C5 (5 coughs in 30 seconds following challenge) is elicited.; TRPA1 agonist will be delivered in serial dilutions as per the clinical trials unit standard operating procedure for cough challenge using KoKo Digidoser, based on ERS guidelines. Challenge will be repeated until C5 (5 coughs in 30 seconds following challenge) is elicited.
Intervention MeSH terms: Citric Acid; Sodium Citrate; Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: chronic; cough; challenge; ATP; hypersensitivity; TRPA1