Effects of Macitentan and Its Active Metabolite on Cultured Human Systemic Sclerosis and Control Skin Fibroblasts

Cutolo, Maurizio; Montagna, Paola; Brizzolara, R.; Smith, Vanessa; Alessandri, Elisa; Villaggio, Barbara; Sulli, Alberto; Tavilla, Pietro Paolo; Pizzorni, Carmen; Soldano, Stefano

doi:10.3899/jrheum.141070

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…These data provide a novel mechanistic interaction between TGF-β and ET-1 and support the concept that ET-1 may play an important pathogenetic role during the earliest stages of development of fibrotic processes involving TGF-β-mediated EndoMT. These results also expand the previously described interactions between TGF-β and ET-1 during normal tissue repair reactions or in the course of organ-specific or systemic pathologic fibrogenesis [59–64]. …”

Section: Discussionsupporting

confidence: 88%

Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1

Wermuth

Mendoza

et al. 2016

PLoS ONE

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TGF-β-induced endothelial-to-mesenchymal transition (EndoMT) is a newly recognized source of profibrotic activated myofibroblasts and has been suggested to play a role in the pathogenesis of various fibrotic processes. Endothelin-1 (ET-1) has been implicated in the development of tissue fibrosis but its participation in TGF-β-induced EndoMT has not been studied. Here we evaluated the role of ET-1 on TGF-β1-induced EndoMT in immunopurified CD31+/CD102+ murine lung microvascular endothelial cells. The expression levels of α-smooth muscle actin (α-SMA), of relevant profibrotic genes, and of various transcription factors involved in the EndoMT process were assessed employing quantitative RT-PCR, immunofluorescence histology and Western blot analysis. TGF-β1 caused potent induction of EndoMT whereas ET-1 alone had a minimal effect. However, ET-1 potentiated TGF-β1-induced EndoMT and TGF-β1-stimulated expression of mesenchymal cell specific and profibrotic genes and proteins. ET-1 also induced expression of the TGF-β receptor 1 and 2 genes, suggesting a plausible autocrine mechanism to potentiate TGF-β-mediated EndoMT and fibrosis. Stimulation of TGF-β1-induced skin and lung fibrosis by ET-1 was confirmed in vivo in an animal model of TGF-β1-induced tissue fibrosis. These results suggest a novel role for ET-1 in the establishment and progression of tissue fibrosis.

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Section: Discussionsupporting

confidence: 88%

Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1

Wermuth

Mendoza

et al. 2016

PLoS ONE

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“…It has been demonstrated that ET receptor antagonists ameliorate bleomycin-induced pulmonary fibrosis [8]. Moreover, in a model of systemic sclerosis (SSc), macitentan inhibited the pro-fibrotic myofibroblast phenotype induced by ET-1 in human skin fibroblasts [25]. Circulating or tissue ET-1 levels are upregulated in IPF and SSc patients and in the bleomycin model of pulmonary fibrosis [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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·day), 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 andOur results demonstrate that dual endothelin receptor antagonism was effective in both PH and lung fibrosis whereas pirfenidone only affected fibrosis.

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“…In particular, for severe RP and for prevention of DU onset and treatment of PAH, both intravenous (IV) prostanoid iloprost (ILO) and the dual endothelin-1 receptor antagonist (ERA) bosentan (BOSE) are used, respectively 10 . BOSE seems to block pathogenic activities of endothelin-1, the endothelial-derived mediator determining both vasoconstriction and fibrosis genes induction 11,12,13,14 .…”

Section: Rheumatologymentioning

confidence: 99%

Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis

Trombetta

Pizzorni²,

Ruaro³

et al. 2016

J Rheumatol

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Objective.To quantify in patients with systemic sclerosis (SSc) the absolute nailfold capillary number/mm (the absolute number of capillaries, observable in the first row, in 1 mm per field) and fingertip blood perfusion (FBP) during longterm therapy with the endothelin receptor antagonist bosentan (BOSE) and the synthetic analog of prostacyclin PGI2 iloprost (ILO) by multiple diagnostic tools. Observed values were correlated with clinical outcomes.Methods.Thirty patients with SSc already receiving intravenous ILO (80 μg/day) for 5 continuous days (every 3 mos) were recruited in the clinic. Fifteen patients continued such treatment (ILO group), while in 15 patients BOSE (125 mg twice/day) was added (ILO + BOSE group) because of the onset of pulmonary arterial hypertension or digital ulcers (DU). The followup period was 4 years (T0–T4). Every year the following were evaluated: absolute nailfold capillary number/mm by nailfold videocapillaroscopy, FBP by laser Doppler flowmetry, DU incidence, DLCO, systolic pulmonary arterial pressure (sPAP), renal arterial resistive index, and other biomarkers. From T2 to T4, laser speckled contrast analysis was added. Nonparametric tests were used for statistical analysis.Results.Limited to the ILO + BOSE group, absolute capillary number/mm and FBP showed a progressive increase independently from other variables. In addition, during followup there was a significant reduction (80%) in the incidence of new DU, whereas DLCO and sPAP did not worsen.Conclusion.The study shows in patients with SSc with up to 4 years of combined therapy a progressive significant recovery in structure and function of microvasculature linked to improved clinical outcomes, independent of disease severity.

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Effects of Macitentan and Its Active Metabolite on Cultured Human Systemic Sclerosis and Control Skin Fibroblasts

Abstract: Macitentan and ACT-132577 seem to downregulate in vitro the profibrotic myofibroblast phenotype induced by ET-1 in cultured human SSc skin fibroblasts.

Cited by 10 publications

References 33 publications

Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1

Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1

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

Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis

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