Calcium-sensing receptor as a therapeutic target for pulmonary fibrosis

Wolffs, Kasope; Mansfield, Bethan; Scofield, Simon; Ward, Jeremy P. T.; Corrigan, Christopher; Prakash, Y. S.; Kemp, Paul J.; Riccardi, Daniela

doi:10.1183/13993003.congress-2018.oa5365

Cited by 3 publications

(3 citation statements)

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“…Mitochondrial calcium signaling can also drive myofibroblast differentiation and fibrosis foci [ 68 ]. Calcium sensitive receptors are upregulated in activated lung fibroblasts that calcilytics reduce markers implicated in pulmonary fibrosis [ 69 ].…”

Section: Crosstalk Between the Ecm And Mitochondria In Ipfmentioning

confidence: 99%

The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis

Siekacz

Piotrowski

Iwański

et al. 2021

Oxidative Medicine and Cellular Longevity

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Idiopathic pulmonary fibrosis (IPF) is a condition which affects mainly older adults, that suggests mitochondrial dysfunction and oxidative stress, which follow cells senescence, and might contribute to the disease onset. We have assumed pathogenesis associated with crosstalk between the extracellular matrix (ECM) and mitochondria, mainly based on mitochondrial equilibrium impairment consisting of (1) tyrosine kinases and serine-threonine kinase (TKs and ST-Ks) activation via cytokines, (2) mitochondrial electron transport chain dysfunction and in consequence electrons leak with lower ATP synthesis, (3) the activation of latent TGF-β via αVβ6 integrin, (4) tensions transduction via α2β1 integrin, (5) inefficient mitophagy, and (6) stress inhibited biogenesis. Mitochondria dysfunction influences ECM composition and vice versa. Damaged mitochondria release mitochondrial reactive oxygen species (mtROS) and the mitochondrial DNA (mtDNA) to the microenvironment. Therefore, airway epithelial cells (AECs) undergo transition and secrete cytokines. Described factors initiate an inflammatory process with immunological enhancement. In consequence, local fibroblasts exposed to harmful conditions transform into myofibroblasts, produce ECM, and induce progression of fibrosis. In our review, we summarize numerous aspects of mitochondrial pathobiology, which seem to be involved in the pathogenesis of lung fibrosis. In addition, an increasing body of evidence suggests considering crosstalk between the ECM and mitochondria in this context. Moreover, mitochondria and ECM seem to be important players in the antifibrotic treatment of IPF.

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Section: Crosstalk Between the Ecm And Mitochondria In Ipfmentioning

confidence: 99%

The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis

Siekacz

Piotrowski

Iwański

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…In addition, Mukherjee et al have demonstrated that the antifibrotic effect of prostaglandin E 2 was associated with interference with calcium-signaling and CaMK-II activation ( Mukherjee et al, 2019 ). An inappropriate calcium response has been linked to IPF through the G protein-coupled calcium sensing receptor (CaSR) ( Wolffs et al, 2019 ). Schuliga et al have demonstrated the association of the calcium binding protein annexin A2 with regional fibrosis in IPF patients and linked it to cytokine production and fibrogenic gene expression ( Schuliga et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Wild-type S100A3 and S100A13 restore calcium homeostasis and mitigate mitochondrial dysregulation in pulmonary fibrosis patient-derived cells

Al-Mutairy,

Al Qattan,

Khalid

et al. 2023

Front. Cell Dev. Biol.

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Patients with digenic S100A3 and S100A13 mutations exhibited an atypical and progressive interstitial pulmonary fibrosis, with impaired intracellular calcium homeostasis and mitochondrial dysfunction. Here we provide direct evidence of a causative effect of the mutation on receptor mediated calcium signaling and calcium store responses in control cells transfected with mutant S100A3 and mutant S100A13. We demonstrate that the mutations lead to increased mitochondrial mass and hyperpolarization, both of which were reversed by transfecting patient-derived cells with the wild type S100A3 and S100A13, or extracellular treatment with the recombinant proteins. In addition, we demonstrate increased secretion of inflammatory mediators in patient-derived cells and in control cells transfected with the mutant-encoding constructs. These findings indicate that treatment of patients’ cells with recombinant S100A3 and S100A13 proteins is sufficient to normalize most of cellular responses, and may therefore suggest the use of these recombinant proteins in the treatment of this devastating disease.

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“…The selective chitinase inhibitor OATD-01 reduced lung fibrosis in a mouse model and had an acceptable safety profile in healthy volunteers [1, 2]. W olffs et al [3] showed that the calcium-sensing receptor (CaSR) is upregulated in IPF lungs and CaSR antagonists reduced fibrotic markers in vitro . A phase 1 study demonstrated an acceptable safety profile of aerosolised pirfenidone in healthy volunteers and IPF patients, with higher concentrations of pirfenidone in epithelial lining fluid and lower plasma levels compared with oral pirfenidone [4].…”

Section: Introductionmentioning

confidence: 99%

Research highlights from the 2018 ERS International Congress: interstitial lung diseases

et al. 2019

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This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD).

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Calcium-sensing receptor as a therapeutic target for pulmonary fibrosis

Cited by 3 publications

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The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis

The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis

Wild-type S100A3 and S100A13 restore calcium homeostasis and mitigate mitochondrial dysregulation in pulmonary fibrosis patient-derived cells

Research highlights from the 2018 ERS International Congress: interstitial lung diseases

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