A novel TRPA1 antagonist inhibits ovalbumin-induced bronchoconstriction in guinea pig models
New therapies (English)Background and Aim: TRPA1 channels are suggested to contribute to airway hyperresponsiveness (AHR) and inflammation in asthma. Here, we evaluated the efficacy of a novel TRPA1 antagonist and investigated how using this antagonist could alleviate symptoms of asthma.
Method: First, a guinea pig model of acute allergic asthma was used to find the optimal dose of the TRPA1 antagonist. In a follow-up study, the effect of TRPA1 antagonist treatment on AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), magnitude of EAR and LAR and airway inflammation was assessed. Thereafter, precision-cut lung slices of ovalbumin sensitized guinea pigs were used to investigate the effect of TRPA1 antagonism on allergen-induced airway narrowing and histamine release.
Results: 1 mg/kg TRPA1 antagonist was selected to be the optimal dose based on AHR data. This was confirmed by exposure data demonstrating that the blood concentration at the time of challenge was around the in vitro IC90 value. We found this dose to inhibit AHR after the EAR by 51%, as well as the development of the EAR and LAR (30% and 36% inhibition respectively). The TRPA1 antagonist did not inhibit total and differential cell counts in the lavage fluid and IL-13 gene expression in lung homogenates. Furthermore, TRPA1 antagonism was able to inhibit allergen-induced airway narrowing in guinea pig lung slices in a dose-dependent manner, without affecting histamine release.
Conclusions: TRPA1 inhibition protects against AHR and the early and late asthmatic response in vivo, and allergen-induced airway narrowing ex vivo via a histamine independent mechanism. This makes TRPA1 an interesting target for asthma therapy.