Pro‐fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system

Ahmedat, As S.; Warnken, Mareille; Seemann, W. K.; Mohr, Klaus; Kostenis, Evi; Juergens, Uwe R.; Racké, Kurt

doi:10.1111/j.1476-5381.2012.02190.x

Cited by 22 publications

(8 citation statements)

References 32 publications

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“…It is well documented that the activation of TGF-β intracellular transcription factors is responsible of the production of other fibrotic molecules, such as ET-1 [ 16 ]. Moreover, TGF-β-induced ET-1 release has been associated with the fibrotic response of skin and lung SSc fibroblasts [ 17 ]. In the present study, we established an in vitro model of EndoMT made up of fibroblast and microvascular endothelial cell (MVEC) cocultures.…”

Section: Introductionmentioning

confidence: 99%

Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study

et al. 2016

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BackgroundSystemic sclerosis (SSc) is characterized by early vascular abnormalities and subsequent fibroblast activation to myofibroblasts, leading to fibrosis. Recently, endothelial-to-mesenchymal transition (EndoMT), a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype, has been reported in SSc. In the present study, we evaluated the ability of endothelin-1 (ET-1) dual receptor antagonists bosentan (BOS) and macitentan (MAC) to antagonize EndoMT in vitro.MethodsTen women with limited SSc were enrolled. They underwent double skin biopsy (affected and nonaffected skin). Fibroblasts and microvascular endothelial cells (MVECs) were isolated from biopsies. We performed mono- or coculture of MVECs (isolated from nonaffected skin) with fibroblasts (isolated from affected skin and stimulated with ET-1 and transforming growth factor beta [TGF-β]). In cocultures, the MVEC layer was left undisturbed or was preincubated with BOS or MAC. After 48 h of coculture, MVECs were analyzed for their tube formation ability and for messenger RNA and protein expression of different vascular (CD31, vascular endothelial growth factor-A [VEGF-A], VEGF-A165b) and profibrotic (alpha-smooth muscle actin [α-SMA], collagen type I [Col I], TGF-β) molecules.ResultsAfter 48 h, MVECs showed a reduced tube formation ability when cocultured with SSc fibroblasts. CD31 and VEGF-A resulted in downregulation, while VEGF-A165b, the antiangiogenic isoform, resulted in upregulation. At the same time, mesenchymal markers α-SMA, Col I, and TGF-β resulted in overexpression in MVECs. Tube formation ability was restored when MVECs were preincubated with BOS or MAC, also reducing the expression of mesenchymal markers and restoring CD31 expression and the imbalance between VEGF-A and VEGF-A165b.ConclusionsWith this innovative EndoMT in vitro model realized by coculturing nonaffected MVECs with affected SSc fibroblasts, we show that the presence of a myofibroblast phenotype in the fibroblast layer, coupled with an ET-1-TGF-β synergic effect, is responsible for EndoMT. BOS and MAC seem able to antagonize this phenomenon in vitro, confirming previous evidence of endothelium-derived fibrosis in SSc and possible pharmacological interference.

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Section: Introductionmentioning

confidence: 99%

Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study

et al. 2016

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“…Recent findings have demonstrated that human lung fibroblasts are fully able to respond to ET-1 in a functional autocrine and paracrine way, as well as expressing preproendothelin and processing this to active ET-1 [18]. Human fibroblasts also express functional ET receptors that can regulate pro-fibrotic features.…”

Section: Bifunctional Bronchodilator Drugsmentioning

confidence: 99%

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Page

Cazzola

2014

Eur Respir J

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Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting b 2 -agonist and an inhaled corticosteroid, and combinations of long-acting b 2 -agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of ''triple-inhaler'' fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called ''bifunctional drugs''. In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/antiinflammatory drugs and bifunctional anti-inflammatory drugs. @ERSpublications Bifunctional drugs offer an exciting new approach to the treatment of asthma and COPD

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“…Upon binding receptors on vascular smooth muscle cells, ET-1 is able to induce vasoconstriction, cell growth, and proliferation, leading to lumen narrowing at arterial and arteriolar level [ 18 – 20 ]. Moreover, ET-1 facilitates fibroblasts transdifferentiation into myofibroblasts and induces the production of both collagen and ET-1 probably through an autocrine mechanism [ 9 , 15 , 21 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis

Tinazzi

Puccetti

Patuzzo

et al. 2015

Journal of Immunology Research

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Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ETB) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects. We studied the expression of ET-1 receptors on immune cells (T and B lymphocytes, monocytes, and neutrophils) and the link between ET-1 and inflammation in patients with SSc. We show here that ET-1 exerts a proinflammatory effect in CD4+ T cells, since it induces an increased IFN-γ production; preincubation with antagonists of both receptors reduces IFN-γ production. Moreover, following ET-1 stimulation, neutrophils produce proinflammatory mediators, thus amplifying the effects of activated CD4+ T cells. Our data indicate that ET-1 system is involved in the pathogenesis of inflammation and fibrosis typical of SSc, through the activation of T lymphocytes and neutrophils and the consequent release of proinflammatory and profibrotic cytokines. These findings suggest that dual ET-1 receptors antagonist therapy, besides its effect on vasculopathy, has a profound impact on the immune system favouring antiinflammatory and antifibrogenic effects.

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Pro‐fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system

Cited by 22 publications

References 32 publications

Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study

Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis

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