An Investigation Into the Mechanism of Inhalation Cough Challenge

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.