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

Tinazzi, Elisa; Puccetti, Antonio; Patuzzo, Giuseppe; Barbieri, Alessandro; Argentino, Giuseppe; Federico, Confente; Dolcino, Marzia; Beri, Ruggero; Marchi, Giacomo; Ottria, Andrea; Righetti, Daniela; Mariaelisa, Rampudda; Lunardi, Claudio

doi:10.1155/2015/147616

Cited by 47 publications

(32 citation statements)

References 43 publications

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“…ET-1 exerts pro-fibrotic effects through the binding to its receptors (ET A and ET B ), which are expressed on several cell types including endothelial cells, fibroblasts and macrophages [13–15]. …”

Section: Introductionmentioning

confidence: 99%

Alternatively Activated (M2) Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages

et al. 2016

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BackgroundAlternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 (CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB). The study investigated the possible role of ET-1 in inducing the transition from cultured human macrophages into M2 cells.MethodsCultured human monocytes (THP-1 cell line) were activated into macrophages (M0 macrophages) with phorbol myristate acetate and subsequently maintained in growth medium (M0-controls) or treated with either ET-1 (100nM) or interleukin-4 (IL-4, 10ng/mL, M2 inducer) for 72 hours. Similarly, primary cultures of human peripheral blood monocyte (PBM)-derived macrophages obtained from healthy subjects, were maintained in growth medium (untreated cells) or treated with ET-1 or IL-4 for 6 days. Both M0 and PBM-derived macrophages were pre-treated with ET receptor antagonist (ETA/BRA, bosentan 10-5M) for 1 hour before ET-1 stimulation. Protein and gene expression of CD204, CD206, CD163, TGFbeta1 were analysed by immunocytochemistry, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Gene expression of interleukin(IL)-10 and macrophage derived chemokine (CCL-22) was evaluated by qRT-PCR. MMP-9 production was investigated by gel zymography.ResultsET-1 significantly increased the expression of M2 phenotype markers CD204, CD206, CD163, IL-10 and CCL-22, and the production of MMP-9 in both cultures of M0 and PBM-derived macrophages compared to M0-controls and untreated cells. In cultured PBM-derived macrophages, ET-1 increased TGFbeta1 protein and gene expression compared to untreated cells. The ET-1-mediated effects were contrasted by ETA/BRA treatment in both cultured cell types.ConclusionET-1 seems to induce the M2 phenotype in cultured human macrophages, a process apparently contrasted by the action of the ETA/BRA, suggesting possible clinical implications in those fibrotic diseases characterized by increased ET-1 concentrations, such as systemic sclerosis but also type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Alternatively Activated (M2) Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages

et al. 2016

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“…There are several studies that show that bosentan inhibits endothelin 1-induced IFNgamma release from CD4+ cells (105) or endotoxin-stimulated cytokine release from pulmonary arterial smooth muscle cells (106), however, Brun et al assessed the systemic inflammatory response in congenital heart disease -associated PAH patients and found no effect of bosentan treatment inflammation (107). …”

Section: Does Targeted Therapy For Pah Modify Inflammation?mentioning

confidence: 99%

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

Voelkel

Tamošiūnienė

Nicolls

2016

Expert Review of Cardiovascular Therapy

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Inflammatory cells are present in the lungs from patients with many, if not all, forms of severe pulmonary hypertension. Historically the first inflammatory cell identified in the pulmonary vascular lesions was the mast cell. T and B lymphocytes, as well as macrophages, are present in and around the pulmonary arterioles and many patients have elevated blood levels of interleukin 1 and 6; some patients show elevated levels of leukotriene B4. An overlap between collagen-vascular disease-associated pulmonary arterial hypertension (PAH) and idiopathic PAH exists, yet only a few studies have been designed that evaluate the effect of anti-inflammatory treatments. Here we review the pertinent data that connect PAH and inflammation/immune dysregulation and evaluate experimental models of severe PAH with an emphasis on the Sugen/athymic rat model of severe PAH. We postulate that there are more than one inflammatory phenotype and predict that there will be several anti-inflammatory treatment strategies for severe PAH.

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“…Pulmonary fibrosis is a very common end-stage manifestation of several diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension, and scleroderma345.…”

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confidence: 99%

Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway

Liu

Chu

et al. 2016

Sci Rep

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Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis.

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

Cited by 47 publications

References 43 publications

Alternatively Activated (M2) Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages

Alternatively Activated (M2) Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway

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