Abstract
Introduction: We previously implicated the calcium-sensing receptor (CaSR) in the development of airways inflammation and hyperresponsiveness in human asthma, and that topical CaSR antagonists (calcilytics) reduce both in animal surrogates.
Aim: Extend these studies to alarmin-driven airways inflammation by comparing the efficacy of topical (intranasal) calcilytic in a head-to-head comparison in Th2/IgE mediated (OVA) and alarmin (interleukin (IL)-33) driven asthma in a murine surrogate.
Methods: IL-33 (naïve mice) or OVA (mice IgE-sensitised to OVA) was delivered once daily intranasally for 6 consecutive days followed by the calcilytic NPSP795 or vehicle control twice daily. On day 7, airways resistance was measured (Flexivent) under anaesthesia then the animals euthanised, after which bronchoalveolar lavage fluid (BALF) was collected, one lung paraffin-embedded for histomorphology and the other homogenised to measure cytokines.
Results: Topical calcilytic significantly reduced (1) airways hyperresponsiveness (both stimuli); (2) BALF total and differential eosinophil, neutrophil and lymphocyte counts and lung homogenate concentrations of IL-5, IL-13 and IL-6 (variable according to stimulus); (3) peribronchial inflammatory cellular infiltration in the OVA, but not the IL-33 driven model; (4) airways collagen deposition in the IL-33, but not the OVA driven model.
Conclusions: Calcilytics show therapeutic benefit in both IgE/Th2 and alarmin-driven airways inflammation and hyperresponsiveness in animal asthma surrogates in vivo, suggesting that they will be effective against any stimulus potentially exacerbating human asthma by inducing an alarmin response in the airways.
Footnotes
Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, OA4958.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2019