Division of Respiratory and Critical Care Medicine, Southwest Medical University, Luzhou City, Sichuan Province, China.
Division of Geriatrics, Chongqing General Hospital, Chongqing Municipality, China.
Adv Rheumatol. 2023 May 16;63(1):22. doi: 10.1186/s42358-023-00305-3.
Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by fibrosis and vascular lesions. Interstitial lung disease is an early complication of SSc and the main cause of death from SSc. Although baricitinib shows good efficacy in a variety of connective tissue diseases, its role in systemic sclerosis-related interstitial lung disease (SSc-ILD) is unclear. The objective of our study was to explore the effect and mechanism of baricitinib in SSc-ILD.
We explored crosstalk between the JAK2 and TGF-β1 pathways. In vivo experiments, SSc-ILD mice model were constructed by subcutaneous injection of PBS or bleomycin (7.5 mg/kg) and intragastric administration of 0.5% CMC-Na or baricitinib (5 mg/kg) once every two days. We used ELISA, qRT‒PCR, western blot and immunofluorescence staining to evaluate the degree of fibrosis. In vitro experiments, we used TGF-β1 and baricitinib to stimulate human fetal lung fibroblasts (HFLs) and assessed protein expression by western blot.
The vivo experiments showed that baricitinib notably alleviated skin and lung fibrosis, decreased the concentration of pro-inflammatory factors and increased those of the anti-inflammatory factors. Baricitinib affected the expression of TGF-β1 and TβRI/II inhibitiing JAK2. In the vitro experiments, following the culture of HFLs with baricitinib or a STAT3 inhibitor for 48 h, the expression levels of TβRI/II decreased. Conversely, with successful inhibition of TGF-β receptors in HFLs, JAK2 protein expression decreased.
Baricitinib attenuated bleomycin-induced skin and lung fibrosis in SSc-ILD mice model by targeting JAK2 and regulating of the crosstalk between the JAK2 and TGF-β1 signaling pathways.
系统性硬化症（SSc）是一种免疫介导的风湿性疾病，其特征为纤维化和血管病变。间质性肺病是 SSc 的早期并发症，也是 SSc 死亡的主要原因。尽管巴瑞替尼在多种结缔组织疾病中显示出良好的疗效，但它在系统性硬化症相关间质性肺病（SSc-ILD）中的作用尚不清楚。本研究旨在探讨巴瑞替尼在 SSc-ILD 中的作用及机制。
我们探讨了 JAK2 和 TGF-β1 通路之间的串扰。体内实验中，通过皮下注射 PBS 或博来霉素（7.5mg/kg）构建 SSc-ILD 小鼠模型，并给予 0.5%CMC-Na 或巴瑞替尼（5mg/kg）灌胃，每两天一次。我们使用 ELISA、qRT-PCR、western blot 和免疫荧光染色来评估纤维化程度。体外实验中，我们使用 TGF-β1 和巴瑞替尼刺激人胚肺成纤维细胞（HFLs），并通过 western blot 评估蛋白表达。
体内实验表明，巴瑞替尼显著缓解皮肤和肺纤维化，降低促炎因子浓度，增加抗炎因子浓度。巴瑞替尼影响 TGF-β1 和 TβRI/II 的表达，抑制 JAK2。在体外实验中，用巴瑞替尼或 STAT3 抑制剂培养 HFLs 48h 后，TβRI/II 的表达水平下降。相反，在 HFLs 中成功抑制 TGF-β 受体后，JAK2 蛋白表达下降。
巴瑞替尼通过靶向 JAK2 并调节 JAK2 和 TGF-β1 信号通路的串扰，减轻 SSc-ILD 小鼠模型中博来霉素诱导的皮肤和肺纤维化。
