Calcium-sensing receptor as a therapeutic target for pulmonary fibrosis

Abstract

Introduction: Pulmonary fibrosis is a symptom of chronic lung diseases characterised by excessive extracellular matrix deposition resulting in the decline of lung function. Idiopathic pulmonary fibrosis (IPF), the most notable, usually results in death within 5 years and currently has no effective treatments. Aims: The extracellular calcium-sensing receptor (CaSR) has been shown to play a role in pathological activation of cardiac fibroblasts and to drive inflammatory lung disease. However, the role of the CaSR in IPF remains unelucidated. This study investigates the role of CaSR in lung fibroblast activation and whether CaSR antagonists, calcilytics, attenuate this process. Methods: Human lung fibroblasts were treated with transforming growth factor-β1 (TGF-β1) in the presence or absence of calcilytic for 72 hours. qPCR, immunofluorescence, ELISA, histology and Western blot analyses were used to assess mRNA and protein expression of CaSR and known fibrotic markers. Results: CaSR is increased in human IPF lungs when compared to control. In human lung fibroblasts, mRNA levels of α-smooth muscle actin and collagen 1 were significantly reduced by calcilytics compared to control (p Conclusions: Our results are the first to report that functional CaSR is up-regulated in activated lung fibroblasts and that calcilytics reduce markers implicated in pulmonary fibrosis. Thus, CaSR may represent a novel therapeutic target in pulmonary fibrosis.