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

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.

• Authors: Jingang Huang, Christiane Maier, Yun Zhang, Alina Soare, Clara Dees, Christian Beyer, Ulrike Harre, Chih-Wei Chen, Oliver Distler, Georg Schett, Lutz Wollin, Jörg H W Distler
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 76 Issue 11 Pg. 1941-1948 (Nov 2017) ISSN: 1468-2060 [Electronic] England
• PMID: 28814429 (Publication Type: Journal Article)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Enzyme Inhibitors
• Fos-Related Antigen-2
• Fosl2 protein, mouse
• Indoles
• Vascular Endothelial Growth Factor A
• Protein-Tyrosine Kinases
• nintedanib

Topics

• Animals
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Fibrosis
• Fos-Related Antigen-2
• Hypertension, Pulmonary (drug therapy, etiology)
• Indoles (pharmacology)
• Macrophage Activation (drug effects)
• Mice
• Mice, Transgenic
• Muscle, Smooth, Vascular (cytology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pulmonary Artery (drug effects)
• Scleroderma, Systemic (complications, drug therapy, pathology)
• Vascular Endothelial Growth Factor A (blood)