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A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis

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posted on 2018-01-10, 12:05 authored by Katy M. Roach, Amanda Sutcliffe, Laura Matthew, Gill Elliot, Chris Newby, Yassine Amrani, Peter Bradding
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. KCa3.1 ion channels play a critical role in TGF1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective KCa3.1 blocker senicapoc. 2 mm3 pieces of human lung parenchyma were cultured for 7 days in DMEM ± TGFβ1 (10 ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. Following 7 days of culture with TGFβ1, 41 IPF- and fibrosis-associated genes were significantly upregulated. Immunohistochemical staining demonstrated increased expression of ECM proteins and fibroblast-specific protein after TGFβ1-stimulation. Collagen secretion was significantly increased following TGFβ1-stimulation. These pro-fibrotic responses were attenuated by senicapoc, but not by dexamethasone. This 7 day ex vivo model of human lung fibrogenesis recapitulates pro-fibrotic events evident in IPF and is sensitive to KCa3.1 channel inhibition. By maintaining the complex cell-cell and cell-matrix interactions of human tissue, and removing cross-species heterogeneity, this model may better predict drug efficacy in clinical trials and accelerate drug development in IPF. KCa3.1 channels are a promising target for the treatment of IPF.

Funding

This work was supported by The Dunhill Medical Trust, project grant R270/1112, the MRC, project grant MR/K018213/1, and The British Lung Foundation, grant PPRG15-8. The work was also supported in part by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit.

History

Citation

Scientific Reports, 2018, 8:342

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

  • VoR (Version of Record)

Published in

Scientific Reports

Publisher

Nature Publishing Group

issn

2045-2322

eissn

2045-2322

Acceptance date

2017-12-14

Copyright date

2017

Available date

2018-02-07

Publisher version

https://www.nature.com/articles/s41598-017-18555-9

Language

en

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