Urban Particulate Matter (PM) is a prominent environmental pollutant implicated in the pathogenesis of obstructive airway disease. We hypothesised that metal cations in PM act at the Calcium-Sensing Receptor (CaSR) in the lung to drive airway inflammation and remodelling.

We have demonstrated that PM contains many CaSR activators. In human population studies, environmental exposure to calcium ions at concentrations found within ambient PM correlates directly with the risk of asthma exacerbation. PM directly activates the human CaSR in stably transfected HEK293 cells, an effect inhibited by CaSR negative allosteric modulators (CaSR NAM) and not seen in empty vector-transfected cells. Immunocytochemistry shows that the CaSR is highly expressed on bronchial epithelial cells and pro-inflammatory cells of the human respiratory epithelium. PM induces maturation and activation of human monocyte-derived dendritic cells and expression of alarmins (IL-33 and TSLP) and pro-inflammatory mediators (NLRP3, IL-6 and IL-1β) by human airways epithelial cells, effects abolished by CaSR NAM. In vivo, topical NAM administration significantly reduces airway

obstruction and lung inflammation and remodelling in an IL-33 driven murine model of obstructive airways disease.

Together, these results suggest that some of the effects of PM are mediated at least in part by the CaSR in the airways, where receptor activation by PM drives airway inflammation and remodelling. Prophylactic use of topically delivered CaSR NAMs may halt progression of airway obstruction in individuals living in highly polluted environments at risk of severe asthma and COPD.