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Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis
  1. Jingang Huang1,
  2. Christiane Maier1,
  3. Yun Zhang1,
  4. Alina Soare1,
  5. Clara Dees1,
  6. Christian Beyer1,
  7. Ulrike Harre1,
  8. Chih-Wei Chen1,
  9. Oliver Distler2,
  10. Georg Schett1,
  11. Lutz Wollin3,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Rheumaklinik, University Hospital Zurich, Zurich, Switzerland
  3. 3Boehringer-Ingelheim Pharma, Div. Research Germany, Biberach, Germany
  1. Correspondence to Dr Jörg H W Distler, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, D91054 Erlangen, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Background Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc).

Methods The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation.

Results Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages.

Conclusion Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung disease.

  • scleroderma
  • endothelial
  • macrophages
  • VEGF
  • CSF

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors Design of the study: LW, JHWD. Acquisition of data: JH, CM, YZ, AS, CD, CB, CWC. Interpretation of data: JH, CM, YZ, AS, CD, CB, CWC, UH, OD, GS, LW, JHWD. Manuscript preparation: JH, CM, LW, JHWD.

  • Funding Grants DI 1537/5-1, DI 1537/7-1, DI 1537/8-1, DI 1537/9-1, DI 1537/11-1, DE 2414/2-1 andAK 144/2-1 of the Deutsche Forschungsgemeinschaft, grants A57, and A64 of the IZKF inErlangen, grant 2013.056.1 of the Wilhelm-Sander-Foundation, grants 2014_A47 and2014_A248 of the Else-Kröner-Fresenius-Foundation, grant 2013.056.1 of the Wilhelm SanderFoundation and a Career Support Award of Medicine of the Ernst Jung Foundation.

  • Competing interests OD has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, Medac, Biovitrium, Boehringer Ingelheim, Novartis, 4D Science, Active Biotech, Bayer, Sinoxa, Serodapharm, EpiPharm, GSK, Pharmacyclics and Biogen. LW is an employee of Boehringer-Ingelheim. JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB. JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, Novartis, Sanofi-Aventis and UCB. JHWD is stock owner of 4D Science.

  • Patient consent Obtained.

  • Ethics approval Ethical Committee of the University of Erlangen-Nuremberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The title has been corrected to: Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis.

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