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TGFβ1 induces resistance of human lung myofibroblasts to cell death via downregulation of TRPA1.

journal contribution
posted on 06.05.2021, 14:15 by HS Virk, MS Biddle, DT Smallwood, CA Weston, E Castells, VW Bowman, J McCarthy, Y Amrani, Duffy Sm, P Bradding, KM Roach

Background and purpose

TGFβ1-mediated myofibroblast activation contributes to pathological fibrosis in many diseases including idiopathic pulmonary fibrosis (IPF), where myofibroblast resistance to oxidant-mediated apoptosis is also evident. We therefore investigated the involvement of redox-sensitive TRPA1 ion channels in human lung myofibroblast (HLMF) cell death and TGFβ1-mediated pro-fibrotic responses.

Experimental approach

We studied HLMFs derived from IPF patients and non-fibrotic patient controls, looking at the effect of TGFβ1 stimulation on TRPA1 expression and cell death sensitivity. We also examined a human lung model of TGFβ1-dependent fibrogenesis.

Key results

We found that TRPA1 mRNA, protein and ion currents were expressed in HLMFs derived from both non-fibrotic patient controls and IPF patients, and expression was reduced by TGFβ1. TRPA1 mRNA was also downregulated by TGFβ1 in a human model of lung fibrogenesis. TRPA1 over-expression or activation induced HLMF apoptosis, and TRPA1 activation by H2 O2 induced necrosis. TRPA1 inhibition resulting from TGFβ1 downregulation or pharmacological inhibition protected HLMFs from both apoptosis and necrosis. Lentiviral vector mediated TRPA1 expression was also found to induce sensitivity to H2 O2 induced cell death in a TRPA1-negative HEK293T cell line.

Conclusion and implications

TGFβ1 induces resistance of HLMFs to TRPA1 agonist- and H2 O2 -mediated cell death via downregulation of TRPA1. Our data suggest that therapeutic strategies which prevent TGFβ1-dependent downregulation of TRPA1 may reduce myofibroblast survival in IPF and therefore improve clinical outcomes.

History

Author affiliation

Department of Respiratory Sciences, University of Leicester

Version

AM (Accepted Manuscript)

Published in

British journal of pharmacology

Publisher

Wiley

issn

0007-1188

eissn

1476-5381

Acceptance date

17/03/2021

Copyright date

2021

Available date

30/03/2022

Spatial coverage

England

Language

eng

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