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

Abstract

OBJECTIVES:

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 α-SMA promoter activity and α-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.

CONCLUSIONS:

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.

• Authors: Ilia Atanelishvili, Tanjina Akter, Atsushi Noguchi, Olha Vuyiv, Lutz Wollin, Richard M Silver, Galina S Bogatkevich
• Journal: Clinical and experimental rheumatology (Clin Exp Rheumatol) 2019 Jul-Aug Vol. 37 Suppl 119 Issue 4 Pg. 115-124 ISSN: 0392-856X [Print] Italy
• PMID: 31573469 (Publication Type: Journal Article)

Chemical References

• Indoles
• Protein Kinase Inhibitors
• nintedanib

Topics

• Cells, Cultured
• Fibroblasts (drug effects)
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, etiology)
• Indoles (therapeutic use)
• Lung (cytology)
• Lung Diseases, Interstitial (drug therapy, etiology)
• Protein Kinase Inhibitors (therapeutic use)
• Scleroderma, Systemic (complications)