Abstract
BackgroundAsthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma.MethodsFirst, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann–Whitney U test or One-way nonparametric Kruskal–Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate.ResultsA dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips.ConclusionsTRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.
Highlights
Asthma is a chronic respiratory disease in which the nervous system plays a central role
We demonstrate that BI01305834 protects against airway hyperresponsiveness (AHR) and the early asthmatic response (EAR) and late asthmatic response (LAR) in an acute OA-induced in vivo model, against allergen and histamine-induced airway narrowing in precision cut lung slices, and is able to partially reverse allergen-induced bronchoconstriction in tracheal strips ex vivo
In conclusion, our study shows that the novel antagonist BI01305834 is a potent and selective Transient Receptor Potential Ankyrin 1 (TRPA1) inhibitor that reduces airway hyperresponsiveness and the early and late asthmatic response in vivo
Summary
Asthma is a chronic respiratory disease in which the nervous system plays a central role. Even though existing treatments are suitable for many patients, there is a substantial group of asthmatic patients with unmet medical needs as, despite being prescribed with high-dose antiinflammatory drugs and bronchodilators, their disease remains difficult to control [4]. This often leads to symptom specific-treatment, deconstructing the disease into treatable elements such as airway inflammation, bronchial hyperresponsiveness and cough reflex hypersensitivity, which each ask for a different therapeutic approach [5]. As it has become clear that immune mechanisms are pivotal in asthma pathology, research into other possible key players is of great importance
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