scholarly journals Linagliptin ameliorates pulmonary fibrosis in systemic sclerosis mouse model via inhibition of endothelial-to-mesenchymal transition

2022 ◽  
Author(s):  
Biwei Pei ◽  
Na Zhang ◽  
Tingting Pang ◽  
Gengyun Sun
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Mouse Model ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

scholarly journals Linagliptin Ameliorates Pulmonary Fibrosis in Systemic Sclerosis Mouse Model via Inhibition of Endothelial to Mesenchymal Transition

2021 ◽  
Author(s):  
Biwei Pei ◽  
Na Zhang ◽  
Tingting Pang ◽  
Gengyun Sun
Keyword(s):  
Oxidative Stress ◽  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Mouse Model ◽  
Therapeutic Effects ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
Dpp4 Inhibitor ◽  
Endothelial To Mesenchymal Transition

Abstract Systemic sclerosis (SSc) is a connective tissue disease that often causes pulmonary fibrosis. Dipeptidyl peptidase 4 (DPP4) inhibitor, has shown anti-fibrotic properties in various fibrotic diseases. However, only two studies have reported its anti-fibrosis effects in pulmonary fibrosis, and the mechanism is not completely clear. In the present study, we further investigated the protective effects of linagliptin, a highly specific DPP4 inhibitor, on pulmonary fibrosis in SSc mouse model and the potential mechanisms. The results showed that linagliptin ameliorated pulmonary fibrosis in SSc mouse model, as evidenced by improved pathological changes of lung and body weight loss induced by BLM. Linagliptin also reduced BLM-induced oxidative stress, inflammation in lung in vivo. We revealed that linagliptin attenuated BLM-induced endothelial to mesenchymal transition (EndMT) in vitro and in vivo. BLM-induced enhanced migration ability of endothelial cells was also alleviated by linagliptin. Moreover, we confirmed that the Akt/mammalian target of rapamycin (mTOR) pathway was involved in BLM-induced EndMT in vivo, which was suppressed by linagliptin. In summary, we further confirmed the therapeutic effects of linagliptin on pulmonary fibrosis in SSc mouse model, which is based on its inhibitory effects on EndMT, oxidative stress and inflammation.

scholarly journals A Potential Link Between Oxidative Stress and Endothelial-to-Mesenchymal Transition in Systemic Sclerosis

2018 ◽  
Vol 9 ◽  
Author(s):  
Duong Thi Bich Thuan ◽  
Hatem Zayed ◽  
Ali H. Eid ◽  
Haissam Abou-Saleh ◽  
Gheyath K. Nasrallah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Systemic Sclerosis ◽  
Mesenchymal Transition ◽  
Potential Link ◽  
Endothelial To Mesenchymal Transition

scholarly journals Macrophages Guard Endothelial Lineage by Hindering Endothelial-to-Mesenchymal Transition: Implications for the Pathogenesis of Systemic Sclerosis

2019 ◽  
Vol 203 (1) ◽  
pp. 247-258 ◽  
Author(s):  
Pier Andrea Nicolosi ◽  
Enrico Tombetti ◽  
Anna Giovenzana ◽  
Eleonora Donè ◽  
Eleonora Pulcinelli ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Mesenchymal Transition ◽  
Endothelial Lineage ◽  
Endothelial To Mesenchymal Transition

scholarly journals IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis

2019 ◽  
Vol 54 (3) ◽  
pp. 1900154 ◽  
Author(s):  
Anna Birnhuber ◽  
Slaven Crnkovic ◽  
Valentina Biasin ◽  
Leigh M. Marsh ◽  
Balazs Odler ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Pulmonary Involvement ◽  
Specific Patient ◽  
Alternatively Activated Macrophages ◽  
Alternatively Activated

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1β in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1β were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg−1·day−1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitro.Fra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1β was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.

scholarly journals A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis

2015 ◽  
Vol 21 (16) ◽  
pp. 3716-3726 ◽  
Author(s):  
Seo-Hyun Choi ◽  
Zhen-Yu Hong ◽  
Jae-Kyung Nam ◽  
Hae-June Lee ◽  
Junho Jang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Radiation Induced ◽  
Endothelial To Mesenchymal Transition

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

2016 ◽  
Vol 18 (1) ◽  
Author(s):  
Claudio Corallo ◽  
Maurizio Cutolo ◽  
Bashar Kahaleh ◽  
Gianluca Pecetti ◽  
Antonio Montella ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
In Vitro Study ◽  
Vitro Study ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

scholarly journals The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis

2019 ◽  
Vol 20 (3) ◽  
pp. 619 ◽  
Author(s):  
Yosuke Kanno
Keyword(s):  
Systemic Sclerosis ◽  
Plasminogen Activator ◽  
Vascular Dysfunction ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Mesenchymal Transition ◽  
Type Plasminogen Activator ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Homeostasis

Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc.

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