Antifibrotic efficacy of nintedanib in a cellular model of systemic sclerosis-associated interstitial lung disease

Objective. Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF) and was demonstrated to slow disease progression in patients with IPF by reducing decline in forced vital capacity by 50%. Recently, nintedanib has been reported to exert anti-fibrotic activity on systemic sclerosis (scleroderma, SSc) skin fibroblasts and to diminish skin and lung fibrosis in mouse models. The goal of the present study was to determine the effects of nintedanib on a cellular model of SSc-associated interstitial lung disease (ILD). Methods. Study was performed using lung fibroblasts (LF) isolated from five patients with SSc-ILD and from three control subjects. Results. Nintedanib inhibited LF proliferation and migration in a concentration-and time-dependent manner. The proliferation rate of LF stimulated with PDGF in the presence of nintedanib was reduced 1.9-fold within 24 h as compared to cells stimulated with PDGF alone. Migration of SSc-ILD LF incubated with 100 nM nintedanib was reduced from 62.8 +/- 12.5% to 39.1 +/- 9.0% in the presence of PDGF and from 38.2 +/- 7.9% to 26.6 +/- 7.2% in serum-free medium. Nintedanib attenuated PDGF-induced Ca2+ efflux, reduced alpha-SMA promoter activity and alpha-SMA protein expression. Furthermore, nintedanib blocked PDGF-induced differentiation of normal LF to myofibroblasts, reduced production of collagen and fibronectin, and decreased contractility of SSc-ILD LF in both floating and fixed collagen gels. Conclusion. Our data demonstrate significant antifibrotic efficacy of nintedanib in SSc-ILD LF suggesting that nintedanib has the potential not only to prevent but also to reverse the increased activity of LF consequently attenuating excessive lung fibrosis observed in SSc-ILD.