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
Pulmonary Department, Meir Medical Center, 59 Tchernichovsky Street, Kfar Saba 4428164, Israel.
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Ther Adv Chronic Dis. 2020 Nov 27;11:2040622320968412. doi: 10.1177/2040622320968412. eCollection 2020.
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 and models, in addition to serum samples from patients with IPF.
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.
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 ( < 0.05). Gal-3 expression was higher in samples from IPF patients compared with non-IPF controls at the protein and mRNA levels ( < 0.05). In the mouse model, Gal-3 levels were increased following fibrosis induction and even further increased with the addition of nintedanib, mostly in macrophages ( < 0.05). Patients receiving nintedanib presented with higher Gal-3 serum levels compared with those who did not receive nintedanib ( < 0.05).
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.
特发性肺纤维化（IPF）是一种常见且严重的肺纤维化形式。尼达尼布，一种三重血管激酶抑制剂，已被批准用于治疗IPF。半乳糖凝集素3（Gal-3）可激活多种促纤维化过程。目前，Gal-3抑制剂TD139正在进行II期临床试验。由于这种治疗是在尼达尼布治疗的基础上进行的，因此评估其对Gal-3水平的影响很重要。因此，除了IPF患者的血清样本外，我们还使用细胞和动物模型评估了尼达尼布对Gal-3表达的影响。
通过免疫组化评估IPF和对照组织样本、尼达尼布治疗后的原代人肺成纤维细胞（HLF，10 - 100 nM，定量聚合酶链反应）以及有/无尼达尼布（0.021 - 0.21 mg/kg）的二氧化硅诱导的纤维化小鼠模型中的Gal-3水平。此外，通过酶联免疫吸附测定法（ELISA）分析41例间质性肺疾病患者在有/无尼达尼布治疗情况下的血清样本中的Gal-3水平。
在HLF中添加尼达尼布导致Gal-3、磷酸化信号转导和转录激活因子3（pSTAT3）以及白细胞介素-8 mRNA水平显著升高（P < 0.05）。在蛋白质和mRNA水平上，IPF患者样本中的Gal-3表达高于非IPF对照（P < 0.05）。在小鼠模型中，纤维化诱导后Gal-3水平升高，添加尼达尼布后进一步升高，主要在巨噬细胞中（P < 0.05）。接受尼达尼布治疗的患者与未接受尼达尼布治疗的患者相比，血清Gal-3水平更高（P < 0.05）。
在实验模型以及患者样本中，尼达尼布均会升高Gal-3水平。这些发现凸显了对IPF患者使用联合抑制疗法的可能性。
