Nintedanib Inhibits Contractile Activity Of Lung Myofibroblasts In A Cellular Model Of Scleroderma Associated Pulmonary Fibrosis

Introduction: Activated lung fibroblasts (LF), or myofibroblasts (MF), from patients with systemic sclerosis (SSc) stay pro-fibrotic in culture. In collagen gel they can be used to explore fibrosis in SSc. Contraction of floating or fixed collagen gels resemble the initial phase of MF activation and the late phase of fibrotic scarring, respectively. Nintedanib (NTB) approved for the treatment of idiopathic pulmonary fibrosis was shown to have anti-fibrotic activity. Aim: To determine the effects of NTB on lung MF isolated from SSc patients with lung fibrosis. Materials and Methods: Study was performed using floating and fixed collagen gels populated with LF from 5 patients with SSc associated lung fibrosis and 3 control donors. Results: PDGF stimulates intracellular Ca2+ and activates smooth muscle α-actin (α-SMA) promoter in LF. PDGF does not interfere with actin polymerization and α-SMA organization, but increases α-SMA protein and collagen gel contraction. NTB attenuates PDGF-induced Ca2+ efflux, α-SMA promoter activity, α-SMA protein and collagen gel contraction in LF. NTB has no effects on basal Ca2+, α-SMA promoter or mRNA, but inhibits the baseline of α-SMA protein in SSc MF. Importantly, NTB reduces collagen gel contractions in SSc MF in both floating and fixed collagen gels. Conclusions: NTB blocks PDGF-induced differentiation of normal LF to MF and reduces contractility of SSc lung MF in both floating and fixed collagen gels suggesting that NTB may not only prevent but also reverse excessive matrix deposition that occurs in scleroderma-associated lung fibrosis.