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Article Dans Une Revue Toxicology and Applied Pharmacology Année : 2022

Arsenic trioxide inhibits the functions of lung fibroblasts derived from patients with idiopathic pulmonary fibrosis

Résumé

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal interstitial lung disease. Currently, no treatment can block or reverse the development of lung fibrosis in patients suffering from IPF. Recent studies indicate that arsenic trioxide (ATO), a safe, effective anti-cancer pro-oxidant drug, prevents the differentiation of normal human lung fibroblasts (NHLFs) in vitro and reduces experimental pulmonary fibrosis in vivo. In this context, we investigated the anti-fibrotic effects of ATO on the main fibrosis functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and non-IPF (control) HLFs were incubated with 0.01-1 μM ATO and stimulated with pro-fibrotic factors (PDGF-BB or TGF-β1). We measured their rates of proliferation, migration and differentiation and the cell stress response triggered by ATO. ATO did not affect cell viability but strongly inhibited the proliferation and migration of PDGF-BB-stimulated IPF and control HLFs. ATO also prevented myofibroblastic differentiation, as assessed by the expression of α-smooth muscle actin (α-SMA) and collagen-1, and the phosphorylation of SMAD2/3 in TGF-β1-stimulated HLFs. These antifibrotic effects were associated with increased expression of the transcription factor NRF2 and its target genes NQO1 and HMOX1. Genetic silencing of NRF2 inhibited the ATO-induced cell stress response but did not prevent the ATO-dependent inhibition of α-SMA expression in TGF-β1-stimulated HLFs. The results demonstrate that ATO, at concentrations similar to exposure in blood plasma of ATO-treated cancer patients, counteracted pro-fibrotic activities of HLFs from IPF patients. We propose to consider ATO for clinical exploration to define the therapeutic potential in patients with IPF.
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Dates et versions

hal-03629873 , version 1 (12-04-2022)

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Paternité - Pas d'utilisation commerciale

Identifiants

Citer

Audrey Joannes, Claudie Morzadec, Maëla Duclos, Francisco Llamas Gutierrez, Dan Cristian Chiforeanu, et al.. Arsenic trioxide inhibits the functions of lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Toxicology and Applied Pharmacology, 2022, 441, pp.115972. ⟨10.1016/j.taap.2022.115972⟩. ⟨hal-03629873⟩
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