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Macitentan reduces progression of TGF-β1-induced pulmonary fibrosis and pulmonary hypertension

Abstract : Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an unknown cause. Two drugs, nintedanib and pirfenidone, have been shown to slow, but not stop, disease progression. Pulmonary hypertension (PH) is a frequent complication in IPF patients and is associated with poor prognosis. Macitentan is a dual endothelin receptor antagonist that is approved for pulmonary arterial hypertension treatment. We hypothesised that using macitentan to treat animals with pulmonary fibrosis induced by adenoviral vector encoding biologically active transforming growth factor-β1 (AdTGF-β1) would improve the PH caused by chronic lung disease and would limit the progression of fibrosis.Rats (Sprague Dawley) which received AdTGF-β1 were treated by daily gavage of macitentan (100 mg·kg-1·day-1), pirfenidone (0.5% food admix) or a combination from day 14 to day 28. Pulmonary artery pressure (PAP) was measured before the rats were killed, and fibrosis was subsequently evaluated by morphometric measurements and hydroxyproline analysis.AdTGF-β1 induced pulmonary fibrosis associated with significant PH. Macitentan reduced the increase in PAP and both macitentan and pirfenidone stopped fibrosis progression from day 14 to day 28. Macitentan protected endothelial cells from myofibroblast differentiation and apoptosis whereas pirfenidone only protected against fibroblast-to-myofibroblast differentiation. Both drugs induced apoptosis of differentiated myofibroblasts in vitro and in vivoOur results demonstrate that dual endothelin receptor antagonism was effective in both PH and lung fibrosis whereas pirfenidone only affected fibrosis.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01952675
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mercredi 12 décembre 2018 - 12:31:27
Dernière modification le : mercredi 10 juin 2020 - 14:06:52

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Pierre-Simon Bellaye, Toyoshi Yanagihara, Elise Granton, Seidai Sato, Chiko Shimbori, et al.. Macitentan reduces progression of TGF-β1-induced pulmonary fibrosis and pulmonary hypertension. European Respiratory Journal, European Respiratory Society, 2018, 52 (2), pp.1701857. ⟨10.1183/13993003.01857-2017⟩. ⟨hal-01952675⟩

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