Galectin-3 levels are elevated following nintedanib treatment

Gali Epstein Shochet; Alon Pomerantz; David Shitrit; Becky Bardenstein-Wald; Kjetil Ask; Mark Surber; Noa Rabinowicz; Yair Levy; Sydney Benchetrit; Evgeny Edelstein; Tali Zitman-Gal

doi:10.1177/2040622320968412

Galectin-3 levels are elevated following nintedanib treatment

Ther Adv Chronic Dis. 2020 Nov 27:11:2040622320968412. doi: 10.1177/2040622320968412. eCollection 2020.

Authors

Affiliations

¹ Pulmonary Department, Meir Medical Center, 59 Tchernichovsky Street, Kfar Saba 4428164, Israel.
² Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
³ Pulmonary Department, Meir Medical Center, Kfar Saba, Israel.
⁴ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁵ McMaster University, Hamilton, ON, Canada.
⁶ Avalyn Pharma, Seattle, WA, USA.
⁷ Internal Medicine E Department, Meir Medical Center, Kfar Saba, Israel.
⁸ Pathology Department, Meir Medical Center, Kfar Saba, Israel.

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.

Keywords: galectin-3; idiopathic pulmonary fibrosis; in vivo models; nintedanib; signal transducer and activator of transcription 3 (STAT3).