Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis

Huang, Junlong; Maier, Christiane; Zhang, Yun; Soare, Alina; Dees, Clara; Beyer, Christian; Harre, Ulrike; Chen, Chih‐Wei; Distler, Oliver; Schett, Georg; Wollin, Lutz; Distler, Jörg H W

doi:10.1136/annrheumdis-2016-210823

Cited by 156 publications

(145 citation statements)

References 39 publications

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“…Thus, the possibility remain that differences in the administration route of nintedanib may be the cause of the contradictory results. In contrast, Huang et al reported that chronic treatment with nintedanib reduced pulmonary vascular remodeling in the Fos-related antigen-2 mouse model of systemic sclerosis (46), which was supportive of our results. On the other hand, another more recent study showed that chronic treatment with nintedanib of established late-phase PAH, from 8 to 11 weeks, did not improved pulmonary hemodynamics and vascular remodeling in SuHx rats (43).…”

Section: Discussionsupporting

confidence: 91%

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. The inhibitory effects of nintedanib were evaluated both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

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Section: Discussionsupporting

confidence: 91%

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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“…Recently nintedanib, an inhibitor of the receptor tyrosine kinase platelet‐derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor, blocked myofibroblast differentiation and subsequent fibrosis in a mouse model of SSc. Interestingly, these nintedanib‐mediated anti‐fibrotic effects were associated with reduced numbers of M2 macrophages .…”

Section: Macrophagesmentioning

confidence: 99%

The immunopathogenesis of fibrosis in systemic sclerosis

Brown

O’Reilly

2018

Clinical and Experimental Immunology

148

113

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Summary Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterized by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. How these different cell types interact to contribute to SSc is complicated, and can involve cell‐to‐cell interactions and communication via cytokines, including transforming growth factor (TGF)‐β, interleukin (IL)‐6 and IL‐4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis.

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“…Consistently, several lines of evidence have shown that celecoxib was able to promote M2‐M1 macrophage conversion or M2 phenotype recruitment suppression in mouse models of cancer or wound healing, thus providing a clue whereby this agent may be capable of reducing reactive stroma features. Similarly, nintedanib has also demonstrated ability to impair M2 macrophage activation in fibrotic milieu . This drug has also inhibited TGF‐β‐induced fibroblast‐to‐myofibroblast differentiation in studies of idiopathic pulmonary fibrosis, whose microenvironment is reminiscent of cancer‐associated reactive stroma …”

Section: Discussionmentioning

confidence: 99%

“…Similarly, nintedanib has also demonstrated ability to impair M2 macrophage activation in fibrotic milieu. 81 This drug has also inhibited TGF-β-induced fibroblast-to-myofibroblast differentiation in studies of idiopathic pulmonary fibrosis, whose microenvironment is reminiscent of cancer-associated reactive stroma. 62 TGF-β is known as the main inducer of CAF/myofibroblast differentiation during reactive stroma development.…”

Section: Discussionmentioning

confidence: 99%

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

et al. 2018

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Background Chronic inflammation has been implicated in cancer etiology and angiogenesis is stimulated in this disease. In prostate, the crosstalk between malignant epithelial cells and their microenvironment is an essential step of tumorigenesis during which glandular stroma undergo changes designated as reactive stroma. Thus, the aim herewith was to evaluate the effects of associating anti‐inflammatory and antiangiogenic therapies on cancer progression, correlating them with steroid hormone receptor (AR and ERα), reactive stroma (vimentin, αSMA, and TGF‐β), and cell proliferation (PCNA) markers expression in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Methods TRAMP mice (12‐week old) were divided into the groups: Control (TRCON): received the vehicles used for drug dilution; Celecoxib (TRCEL): received oral doses of the anti‐inflammatory drug celecoxib (15 mg/kg) twice daily; Nintedanib (TRNTB): received oral doses of the antiangiogenic drug nintedanib (10 mg/kg) daily; Nintedanib+Celecoxib (TRNTCEL): received the combination of drugs. After 6 weeks, mice were euthanized and ventral prostate samples were harvested for morphological, immunohistochemical, and Western blotting analyses. Results While celecoxib led to fibromuscular hypertrophy attenuation, nintedanib significantly reduced the incidence of well‐differentiated adenocarcinoma (WDAC) foci in relation to controls, both when administered per se or in association to celecoxib. Furthermore, drug combination was associated with unique effects, including lower incidence of HGPIN lesions; lower AR stromal distribution; changes in ERα localization from epithelial nuclei to stroma as well as significant decrease of TGF‐β levels and associated angiogenesis. In parallel, all treatments applied resulted in reduced inflammatory marker and vimentin (VIM) expression. Conclusions Celecoxib plus nintedanib is an effective antitumor combination against prostate cancer progression in TRAMP mice, showing remarkable efficacy in relation to isolated therapies. Importantly, this efficacy might be due to drug association effect on driving AR and mainly ERα distribution in the prostatic tissue towards benign patterns. In addition, celecoxib and nintedanib impaired the development of a stromal reaction by reducing the recruitment of reactive stroma cells and maintaining a normal smooth muscle cell‐rich prostate stroma in TRAMP mice. Collectively, these findings pointed to the beneficial effects of combining anti‐inflammatory and antiangiogenic strategies to prevent or delay prostatic tumorigenesis.

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Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis

Cited by 156 publications

References 39 publications

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

The immunopathogenesis of fibrosis in systemic sclerosis

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

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