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·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.

si-SNHG5-FOXF2 Inhibits TGF-β1-induced Fibrosis in Human Primary Endometrial Stromal Cells by Wnt/β-catenin Signaling Pathway

“…In addition, TGF-β1 can induce the transformation of various cell types, such as vascular endothelial cells, broblasts (FBs) and renal tubular epithelial cells, into α-smooth muscle actin (α-SMA)-expressing myo broblasts (MFs). MFs, which exhibit characteristic of smooth muscle cells and FBs, are generally considered the key source of ECM production during tissue brosis, [12][13][14]. It has been con rmed that TGF-β1 induces the epithelial-mesenchymal transition (EMT) and causes ECM to be excessively deposited as collagen [15][16][17].…”

Is there a role for endothelin-1 receptor antagonists in the treatment of lung fibrosis associated with pulmonary hypertension?

“…These findings point to a potential promise of ET-1 receptor antagonists, and particularly macitentan, in the treatment of IPF and associated PH; yet in both studies ET-1 receptor antagonists were given as prevention rather than treatment, limiting their translational power [8]. Now, BELLAYE et al [4] report elevated circulating levels of ET-1 in IPF patients which correlated with disease severity as assessed by pulmonary function tests. Similarly, expression of the ET-1 receptor A (ETRA) but not of ET-1 receptor B (ETRB) was upregulated in lung tissue of IPF patients as a function of disease stage, suggesting a possible role of ET-1 signalling via ETRA in the disease pathomechanism.…”

“…In a study published in this issue of the European Respiratory Journal, BELLAYE et al [4] now report promising results on the therapeutic efficacy of macitentan, an oral dual endothelin-1 (ET-1) receptor antagonist, in a preclinical model of group 3 PH. Macitentan is approved for the treatment of PAH, where it delays disease progression and clinical worsening [5].…”

“…Macitentan is approved for the treatment of PAH, where it delays disease progression and clinical worsening [5]. Now, BELLAYE et al [4] tested macitentan in a rat model of interstitial pulmonary fibrosis (IPF) with associated PH. Dual endothelin receptor antagonism by bosentan had formerly been shown to attenuate the development of lung fibrosis in the rat bleomycin model [6].…”

“…Next, BELLAYE et al [4] tested for the effects of macitentan in a rat model of pulmonary fibrosis following adenoviral overexpression of transforming growth factor-β1 (AdTGF-β1) [14]. TGF-β1 is the major cytokine driving both lung fibrosis and PH.…”