Arsenic trioxyde inhibits the functions on lung fibroblasts derived from patients with idiopathic pulmonary fibrosis

Nintedanib and pirfenidone have been approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both drugs were shown to reduce but not to stop disease progression. Hence the medical need is still high for new effective anti-fibrotic molecules. Arsenic trioxide (ATO), a safe and effective drug used in cancer therapy, decreased pulmonary fibrosis induced by bleomycin in mice. In order to specify the anti-fibrotic properties of ATO, we investigated its effects on main functions of human lung fibroblasts (HLFs). IPF and control HLFs were derived from lung biopsies isolated from patients with IPF or without intertitial lung disease. After pre-treatment with ATO (0.01-1 μM) and stimulation with PDGF-BB (50 ng/ml) or TGF-β1 (1 ng/ml), proliferation, migration and differentiation of HLFs were assessed as well as the cell stress response triggered by ATO. The metalloid did not affect cell viability but it significantly decreased, in a concentration-dependent manner, the proliferation and migration of control and IPF HLFs induced by PDGF-BB. ATO also prevented the up-regulation of α-SMA, Collagen-1 and p-SMAD3 protein levels in TGF-β1-stimulated HLFs. The metalloid effects were associated with stabilization of the transcription factor NRF2 and induction of the antioxidant proteins NQO1 and HO-1 that emphases the stress response developed by ATO-treated HLFs. In conclusions, our results demonstrate that, in vitro, ATO concentrations, in the range of arsenic plasmatic levels measured in patients treated with standard dosing, counteracts the detrimental functions of IPF HLFs. ATO may thus be taken into consideration as a new therapeutic option for IPF treatment.