Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China; State Key Lab of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Toxicol Lett. 2020 Mar 15;321:103-113. doi: 10.1016/j.toxlet.2019.11.003. Epub 2019 Nov 6.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no effective medication. Andrographolide (Andro), extracted from Chinese herbal Andrographis paniculata, could attenuate bleomycin (BLM)-induced pulmonary fibrosis via inhibition of inflammation and oxidative stress, however, the anti-fibrotic mechanisms have not been clarified. Myofibroblasts are the primary cell types responsible for the accumulation of extracellular matrix (ECM) in fibrotic diseases, and targeting fibroblast proliferation and differentiation is an important therapeutic strategy for the treatment of IPF. Hence, this study aimed to investigate the effects of Andro on the fibroblast proliferation and differentiation in the in vivo and in vitro models. The results showed that Andro improved pulmonary function and inhibited BLM-induced fibroblast proliferation and differentiation and ECM deposition in the lungs. In vitro, Andro inhibited proliferation and induced apoptosis of TGF-β1-stimulated NIH 3T3 fibroblasts and primary lung fibroblasts (PLFs). Andro also inhibited TGF-β1-induced myofibroblast differentiation and ECM deposition in both cells. We also found that Andro suppressed TGF-β1-induced Smad2/3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediates Andro-induced effects on TGF-β1-induced fibroblast proliferation and differentiation. These results indicated that Andro has novel and potent anti-fibrotic effects in lung fibroblasts via inhibition of the proliferation and myofibroblast differentiation of fibroblasts and subsequent ECM deposition, which are modulated by TGF-β1-mediated Smad-dependent and -independent pathways.
特发性肺纤维化（IPF）是一种进行性肺部疾病，目前尚无有效药物。穿心莲内酯（Andro）是从中药穿心莲中提取的一种化合物，可通过抑制炎症和氧化应激来减轻博来霉素（BLM）诱导的肺纤维化，但抗纤维化机制尚不清楚。肌成纤维细胞是导致纤维化疾病中细胞外基质（ECM）积累的主要细胞类型，靶向成纤维细胞增殖和分化是治疗 IPF 的重要治疗策略。因此，本研究旨在探讨穿心莲内酯对体内和体外模型中成纤维细胞增殖和分化的影响。结果表明，穿心莲内酯改善了肺功能，抑制了 BLM 诱导的成纤维细胞增殖和分化以及肺部 ECM 的沉积。在体外，穿心莲内酯抑制 TGF-β1 刺激的 NIH 3T3 成纤维细胞和原代肺成纤维细胞（PLFs）的增殖并诱导其凋亡。穿心莲内酯还抑制了 TGF-β1 诱导的两种细胞中的肌成纤维细胞分化和 ECM 沉积。我们还发现，穿心莲内酯抑制了 TGF-β1 诱导的 Smad2/3 和 Erk1/2 激活，表明 Smad2/3 和 Erk1/2 的失活介导了穿心莲内酯对 TGF-β1 诱导的成纤维细胞增殖和分化的影响。这些结果表明，穿心莲内酯通过抑制成纤维细胞的增殖和肌成纤维细胞分化以及随后的 ECM 沉积，具有新型且有效的抗纤维化作用，这是由 TGF-β1 介导的 Smad 依赖性和非依赖性途径调节的。
