Faculty, Staff and Student Publications
Publication Date
4-1-2025
Journal
Biomolecules
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine-polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing receptor (CaSR), activation of which is detrimental for asthma and pulmonary hypertension, but its role in IPF is unknown. To address this question, we evaluated polyamine abundance using metabolomic analysis of IPF patient saliva. Furthermore, we examined CaSR functional expression in human lung fibroblasts (HLFs), assessed the anti-fibrotic effects of a CaSR antagonist, NPS2143, in TGFβ1-activated normal and IPF HLFs by RNA sequencing and immunofluorescence imaging, respectively; and NPS2143 effects on polyamine synthesis in HLFs by immunoassays. Our results demonstrate that polyamine metabolites are increased in IPF patient saliva. Polyamines activate fibroblast CaSR in vitro, elevating intracellular calcium concentration. CaSR inhibition reduced TGFβ1-induced polyamine and pro-fibrotic factor expression in normal and IPF HLFs. TGFβ1 directly stimulated polyamine release by HLFs, an effect that was blocked by NPS2143. This suggests that TGFβ1 promotes CaSR activation through increased polyamine expression, driving a pro-fibrotic response. By halting some polyamine-induced pro-fibrotic changes, CaSR antagonists exhibit disease-modifying potential in IPF onset and development.
Keywords
Humans, Receptors, Calcium-Sensing, Idiopathic Pulmonary Fibrosis, Fibroblasts, Polyamines, Transforming Growth Factor beta1, Naphthalenes, Lung, Male, Female, Benzamides, Cyclohexylamines, idiopathic pulmonary fibrosis, calcium/cation-sensing receptor, TGFβ1, arginine–polyamine pathway, negative allosteric modulator
DOI
10.3390/biom15040509
PMID
40305220
PMCID
PMC12025166
PubMedCentral® Posted Date
4-1-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes