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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.

In idiopathic pulmonary fibrosis (IPF) breathing pattern changes with disease progress. This study aims to determine if unsupervised hierarchal cluster analysis (HCA) can be used to define airflow profile differences in people with and without IPF. This was tested using 31 patients with IPF and 17 matched healthy controls, all of whom had their lung function assessed using spirometry and carbon monoxide CO transfer. A resting tidal breathing (RTB) trace of two minutes duration was collected at the same time. A Euclidian distance technique was used to perform HCA on the airflow data. Four distinct clusters were found, with the majority (18 of 21, 86%) of the severest IPF participants (Stage 2 and 3) being in two clusters. The participants in these clusters exhibited a distinct minute ventilation (p < 0.05), compared to the other two clusters. The respiratory drive was greatest in Cluster 1, which contained many of the IPF participants. Unstructured HCA was successful in recognising different airflow profiles, clustering according to differences in flow rather than time. HCA showed that there is an overlap in tidal airflow profiles between healthy RTB and those with IPF. The further application of HCA in recognising other respiratory disease is discussed.

Idiopathic pulmonary fibrosis (IPF) is a disease with very poor prognosis and no curative therapies. Central to its progression is the activation of fibroblasts by TGFβ, which initiates various fibrotic processes. The extracellular calcium-sensing receptor (CaSR) is a chemosensor which is activated by several agonists/modulators, including polyvalent cations, polyamines, and basic polypeptides. Previous studies have shown that CaSR activation drives pulmonary inflammation and remodelling in preclinical models of asthma, COPD and pulmonary hypertension. However, the role of the receptor in pulmonary fibrosis remains unknown. During my PhD, I investigated CaSR expression in IPF lung tissue, expression of CaSR activators in PF patient saliva, and the role of the receptor in mediating TGFβ-induced fibrotic response in primary human lung fibroblasts (NHLFs) using a negative allosteric modulator (NAM) of the CaSR, NPS2143. The in vitro studies were carried out using NHLFs treated with TGFβ1 in the presence/absence of NAM or NAM alone for 72 hours. Data from these studies indicate five principal findings: 1. In vivo CaSR expression occurs in the bronchiolar epithelium, proliferated pulmonary neuroepithelial bodies (NEBs), and the interstitium of normal and IPF lungs. 2. Expression of certain CaSR activators, amino acids and polyamines are increased in the saliva of PF patients. Since these ligands can activate the CaSR expressed by epithelial cells or NEBs, our study identifies a potential role for the receptor in IPF pathogenesis. 3. The CaSR is functionally expressed by NHLFs in vitro, suggesting the receptor might contribute to fibrogenesis. 4. TGFβ1 upregulates the expression of key profibrotic and metabolic reprogramming genes in vitro, and the NAM, NPS2143, prevents these changes. 5. NPS2143 prevents the cellular and molecular profibrotic responses (such as fibroblast activation, proliferation, collagen and IL-8 secretion) to TGFβ1 in vitro. Together, these results strongly suggest a role for the CaSR in (I)PF aetiology.