Yang Jin-Yu, Tao Li-Jun, Liu Bei, You Xin-Yi, Zhang Chao-Feng, Xie Hai-Feng, Li Ren-Shi
State Key Laboratory of Natural Medicines, School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, China.
Chengdu Biopurify Phytochemicals Ltd., Chengdu, China.
Front Pharmacol. 2019 Mar 5;10:151. doi: 10.3389/fphar.2019.00151. eCollection 2019.
Pulmonary fibrosis is common in a variety of inflammatory lung diseases, there is currently no effective clinical drug treatment. It has been reported that the ethanol extract of . can improve the lung collagen deposition and fibrosis pathology induced by bleomycin (BLM) in mice. In the present study, we studied whether wedelolactone (WEL), a major coumarin ingredient of , provided protection against BLM-induced pulmonary fibrosis. ICR or C57/BL6 strain mice were treated with BLM to establish lung fibrosis model. WEL (2 or 10 mg/kg) was given daily via intragastric administration for 2 weeks starting at 7-day after intratracheal instillation. WEL at 10 mg/kg significantly reduced BLM-induced inflammatory cells infiltration, pro-inflammatory factors expression, and collagen deposition in lung tissues. Additionally, treatment with WEL also impaired BLM-induced increases in fibrotic marker expression (collagen I and α-SMA) and decrease in an anti-fibrotic marker (E-cadherin). Treatment with WEL significantly prevented BLM-induced increase in TGF-β1 and Smad2/3 phosphorylation in the lungs. WEL administration (10 mg/kg) also significantly promoted AMPK activation compared to model group in BLM-treated mice. Further investigation indicated that activation of AMPK by WEL can suppressed the transdifferentiation of primary lung fibroblasts and the epithelial mesenchymal transition (EMT) of alveolar epithelial cells, the inhibitive effects of WEL was significantly blocked by an AMPK inhibitor (compound C) . Together, these results suggest that activation of AMPK by WEL followed by reduction in TGFβ1/Raf-MAPK signaling pathways may have a therapeutic potential in pulmonary fibrosis.
肺纤维化在多种炎症性肺部疾病中很常见，目前尚无有效的临床药物治疗方法。据报道，[植物名称]的乙醇提取物可以改善博来霉素（BLM）诱导的小鼠肺胶原沉积和纤维化病理。在本研究中，我们研究了[植物名称]的主要香豆素成分水飞蓟宾（WEL）是否能预防BLM诱导的肺纤维化。用BLM处理ICR或C57/BL6品系小鼠以建立肺纤维化模型。从气管内滴注后第7天开始，每天通过灌胃给予WEL（2或10mg/kg），持续2周。10mg/kg的WEL显著减少了BLM诱导的肺组织中炎症细胞浸润、促炎因子表达和胶原沉积。此外，WEL治疗还抑制了BLM诱导的纤维化标志物表达（I型胶原和α-SMA）增加以及抗纤维化标志物（E-钙黏蛋白）减少。WEL治疗显著预防了BLM诱导的肺组织中TGF-β1和Smad2/3磷酸化增加。与BLM处理小鼠的模型组相比，给予WEL（10mg/kg）也显著促进了AMPK激活。进一步研究表明，WEL激活AMPK可抑制原代肺成纤维细胞的转分化和肺泡上皮细胞的上皮-间质转化（EMT），WEL的抑制作用被AMPK抑制剂（化合物C）显著阻断。总之，这些结果表明，WEL激活AMPK，随后降低TGFβ1/Raf-MAPK信号通路，可能对肺纤维化具有治疗潜力。
