Galectin-3 levels are elevated following nintedanib treatment. (November 2020)

• Record Type: Journal Article
• Authors: Shochet, Gali Epstein; Pomerantz, Alon; Shitrit, David; Bardenstein-Wald, Becky; Ask, Kjetil; Surber, Mark; Rabinowicz, Noa; Levy, Yair; Benchetrit, Sydney; Edelstein, Evgeny; Zitman-Gal, Tali
• Is Part Of: Therapeutic advances in chronic disease. Volume 11(2020)
• Publication Date: 2020-11
• Subjects: galectin-3 -- idiopathic pulmonary fibrosis -- in vivo models -- nintedanib -- signal transducer and activator of transcription 3 (STAT3); Chronic diseases -- Periodicals; Chronic diseases -- Treatment -- Periodicals; Chronic Disease -- Periodicals; Chronic Disease -- therapy -- Periodicals; 616.044
• DOI: 10.1177/2040622320968412
• Languages: English
• ISSNs: 2040-6223

Abstract

Background and Aims: Idiopathic pulmonary fibrosis (IPF) is a common and severe form of pulmonary fibrosis. Nintedanib, a triple angiokinase inhibitor, is approved for treating IPF. Galectin 3 (Gal-3) activates a variety of profibrotic processes. Currently, the Gal-3 inhibitor TD139 is being tested in phase II clinical trials. Since this treatment is given 'on top' of nintedanib, it is important to estimate its effect on Gal-3 levels. Therefore, we evaluated the impact of nintedanib on Gal-3 expression using both in vitro and in vivo models, in addition to serum samples from patients with IPF. Methods: Gal-3 levels were evaluated in IPF and control tissue samples, primary human lung fibroblasts (HLFs) following nintedanib treatment (10–100 nM, quantitative polymerase chain reaction), and in a silica-induced fibrosis mouse model with/without nintedanib (0.021–0.21 mg/kg) by immunohistochemistry. In addition, Gal-3 levels were analyzed in serum samples from 41 patients with interstitial lung disease patients with/without nintedanib treatment by ELISA. Results: Nintedanib addition to HLFs resulted in significant elevations in Gal-3, phospho-signal transducer and activator of transcription 3 (pSTAT3), as well as IL-8 mRNA levels ( p < 0.05). Gal-3 expression was higher in samples from IPF patients compared with non-IPF controls at the protein and mRNA levels ( p < 0.05). In the in vivo mouse model, Gal-3 levels were increased following fibrosis induction and even further increased with the addition of nintedanib, mostly in macrophages ( p < 0.05). Patients receiving nintedanib presented with higher Gal-3 serum levels compared with those who did not receive nintedanib ( p < 0.05). Conclusion: Nintedanib elevates Gal-3 levels in both experimental models, along with patient samples. These findings highlight the possibility of using combined inhibition therapy for patients with IPF.