Calcium-sensing receptor antagonism as a novel therapeutic for pulmonary fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with very poor prognosis and no curative therapies. The G protein-coupled, calcium/cation-sensing receptor (CaSR) is activated by environmental pollutants and by arginine-derived polyamines, which are thought to play a role in IPF. Whether the CaSR is involved in the pathogenesis of pulmonary fibrosis is unknown. Objective: To investigate the CaSR as a novel drug target for the treatment of pulmonary fibrosis (PF). Methods and results: CaSR protein expression is found in the airway epithelium in the neuroepithelial bodies of the healthy and IPF human lung. Expression of arginine pathway-linked polyamines is increased in PF patient saliva samples compared to non-PF patients. Arginine pathway metabolites, ornithine and spermine, activate the CaSR in primary normal human lung fibroblasts (NHLF), effects prevented by CaSR antagonism using the calcilytic NPS2143. In NHLF calcilytic also reversed the pro-fibrotic effects of exogenous TGFβ1 administration on Rho kinase and αSMA expression, proliferation, collagen production and IL-8 secretion. Targeted CaSR ablation from fibroblasts and smooth muscle cells protects mice from spontaneously occurring, age-related lung fibrosis. Conclusions: Sustained CaSR activation in the lung drives pro-fibrotic processes, which can be reversed by calcilytic. Pharmacological and genetic CaSR blockade reduce both TGFβ1-induced and naturally occurring pro-fibrotic changes. This work provides the scientific rationale for developing inhaled calcilytics as novel therapeutics for IPF.