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. 2021 Aug;178(15):2948-2962.
doi: 10.1111/bph.15467. Epub 2021 May 25.

TGFβ1 induces resistance of human lung myofibroblasts to cell death via down-regulation of TRPA1 channels

Harvinder S Virk  1 , Michael S Biddle  1 , Dawn T Smallwood  2 , Cathryn A Weston  1 , Emily Castells  1 , Viona W Bowman  2 , Jamie McCarthy  1 , Yassine Amrani  1 , S Mark Duffy  1 , Peter Bradding  1 , Katy M Roach  1
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Free article

TGFβ1 induces resistance of human lung myofibroblasts to cell death via down-regulation of TRPA1 channels

Harvinder S Virk et al. Br J Pharmacol. 2021 Aug.
Free article

Abstract

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 on human lung myofibroblasts (HLMFs) cell death and TGFβ1-mediated pro-fibrotic responses.

Experimental approach: The effects of TGFβ1 stimulation on TRPA1 expression and cell viability was studied in HLMFs derived from IPF patients and non-fibrotic patients. We also examined a model of TGFβ1-dependent fibrogenesis in human lung. We used qRT-PCR, immunofluorescent assays, overexpression with lentiviral vectors and electrophysiological methods.

Key results: 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 down-regulated by TGFβ1 in a model of lung fibrogenesis in human lung. TRPA1 over-expression or activation induced HLMF apoptosis, and activation of TRPA1 channel activation by H2 O2 induced necrosis. TRPA1 inhibition following TGFβ1 down-regulation 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 down-regulation of TRPA1 channels. Our data suggest that therapeutic strategies which prevent TGFβ1-dependent down-regulation of TRPA1 may reduce myofibroblast survival in IPF and therefore improve clinical outcomes.

Keywords: IPF; TGFβ1; TRPA1; apoptosis; fibrosis; myofibroblast; oxidative stress.

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