Determining the role of the calcium-sensing receptor (CASR) in pulmonary fibrosis (PF) and the ability of a CASR inhibitor to reverse profibrotic changes in an in vitro model of PF

Wolffs, Kasope Lucy 2022. Determining the role of the calcium-sensing receptor (CASR) in pulmonary fibrosis (PF) and the ability of a CASR inhibitor to reverse profibrotic changes in an in vitro model of PF. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

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

Item Type:	Thesis (PhD)
Date Type:	Acceptance
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	28 July 2022
Date of Acceptance:	2022
Last Modified:	01 Aug 2022 10:33
URI:	https://orca.cardiff.ac.uk/id/eprint/151537

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