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

Abstract

BackgroundNintedanib 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).MethodsThe 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.ResultsNintedanib 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.ConclusionNintedanib 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.