Calcium-sensing receptor (CaSR) drives lung ECM remodelling and fibrosis in murine asthma models and in ageing mice

Abstract

Background: Structural changes such as sub-epithelial fibrosis occur in inflammatory lung disease and as a natural process in the ageing lung. We have previously shown that activation of the CaSR drives inflammation in in vivo models of inflammatory lung disease, and that negative allosteric modulators of the CaSR, termed calcilytics, reduce these effects. Whether CaSR activation also contributes to extracellular matrix (ECM) remodelling and age-related fibrosis is unknown. Aim: To determine the role of the CaSR in ECM remodelling using in vivo models of allergic and non-allergic asthma and of age-related fibrosis. Methods: Ovalbumin-sensitised/challenged and IL33-sensitised mice as well as 15-month-old mice with targeted CaSR deletion from myofibroblasts and smooth muscle cells (achieved using an sm22a Cre promoter) were used as models of allergic asthma, non-allergic asthma and age-related fibrosis, respectively. Masson’s trichrome staining with semi-quantitative histomorphometry was employed to determine collagen expression beneath the airway epithelium of small and large airways. Results: Calcilytic treatment significantly reduced subepithelial collagen deposition in both large and small airways of ovalbumin-challenged mice and in large, but not small airways of IL33-sensitised mice (p Conclusions: CaSR activation drives pulmonary remodelling and fibrosis in animal models of asthma and in ageing mice. In addition to reducing inflammation, calcilytics might prove beneficial at reducing ECM remodelling during inflammatory lung disease.