Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterised by fibroblast activation, extracellular matrix deposition and inflammatory cell recruitment. Altered metabolism, including dysregulation of the arginine–polyamine pathway, is increasingly recognised in IPF. Polyamines are endogenous agonists of the calcium-sensing receptor (CaSR), a G protein-coupled receptor implicated in pulmonary inflammation and remodelling. Our previous work demonstrated altered polyamine metabolism in IPF and showed that polyamines activate CaSR-dependent signalling in human lung fibroblasts, while pharmacological CaSR inhibition attenuates TGFβ1-induced profibrotic responses and associated transcriptional changes (1).
Building on these findings, we aimed to determine how CaSR signalling contributes to inflammatory and fibrotic responses through distinct cellular compartments in vivo. Mice with conditional deletion of CaSR in MRP8-expressing myeloid cells or PDGFRβ-expressing mesenchymal cells underwent bleomycin-induced lung injury. Bronchoalveolar lavage fluid (BALF) was assessed for cellularity, soluble collagen, TGFβ, spermine and ornithine. Bleomycin increased BALF cellularity, soluble collagen, TGFβ, spermine and ornithine in control mice.
Mesenchymal CaSR deletion reduced soluble collagen and spermine while increasing ornithine, without significantly altering BALF cellularity or TGFβ. In contrast, myeloid CaSR deletion reduced BALF cellularity, TGFβ and spermine, while soluble collagen and ornithine were unchanged. Together with our previous human fibroblast studies, these findings support a model in which CaSR links altered polyamine metabolism with inflammatory and fibrotic remodelling through cell-specific mechanisms.
The major outcome of this study is that CaSR contributes to pulmonary fibrosis through complementary pathways, regulating profibrotic signalling and collagen accumulation in mesenchymal cells while promoting inflammatory recruitment and TGFβ responses through myeloid cells.