Late Breaking Abstract - Calcium-sensing receptor activators increased in the sputum of idiopathic pulmonary fibrosis patients

Introduction: Idiopathic pulmonary fibrosis (IPF) is an incurable disease with very poor prognosis and no curative therapies. The extracellular calcium-sensing receptor (CaSR) has been shown to drive pulmonary remodelling in preclinical models of pulmonary hypertension and inflammatory lung diseases. CaSR activation is induced by endogenous and exogenous polycations (polyamines and positively-charged environmental pollutants, respectively). However, the role of CaSR in IPF requires further investigation. Methods: Immunostaining was used to assess lung CaSR expression in IPF patients and control. CaSR-related metabolites were assessed in patient saliva samples (IPF and control) using high-resolution mass spectrometry. Histology was carried out in old mice with targeted CaSR deletion to assess age-induced lung remodelling. In human lung fibroblasts (HLF), the polyamine, spermine, was used to assess CaSR activation via calcium imaging. Results: Differential CaSR expression was observed in IPF lungs compared to controls. Several CaSR activators (amines and polyamines) were significantly increased in IPF patients compared to control (p<0.05). Selective CaSR deletion protected mice from age-induced fibrosis (p<0.05). CaSR is expressed and functional in human lung fibroblasts; receptor activation was blocked in the presence of calcilytics. Conclusions: This study supports the role of the CaSR in PF, as receptor deletion resulted in reduced fibrosis. Since CaSR activators are elevated in IPF patient saliva, increased levels of these metabolites suggest a role for the CaSR in the pathophysiology of IPF. Although further work is required, our results highlight CaSR as a therapeutic target for IPF.