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Lookup NU author(s): Professor John SimpsonORCiD, Dr Polina YarovaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors.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.
Author(s): Wolffs K, Li R, Mansfield B, Pass DA, Bruce RT, Huang P, de Araujo RP, Haddadi BS, Mur LAJ, Dally J, Moseley R, Ecker R, Karmouty-Quintana H, Lewis KE, Simpson AJ, Ward JPT, Corrigan CJ, Jurkowska RZ, Hope-Gill BD, Riccardi D, Yarova PL
Publication type: Article
Publication status: Published
Journal: Biomolecules
Year: 2025
Volume: 15
Issue: 4
Print publication date: 01/04/2025
Online publication date: 01/04/2025
Acceptance date: 19/03/2025
Date deposited: 13/05/2025
ISSN (electronic): 2218-273X
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
URL: https://doi.org/10.3390/biom15040509
DOI: 10.3390/biom15040509
Data Access Statement: The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author(s). Bioinformatics data presented in this study are openly available in NCBI Sequence Read Archive (SRA) at https://www.ncbi.nlm.nih.gov/sra/ (accessed on 18 March 2025) or accession number: PRJNA1213828.
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