Tao Lijun, Yang Jinyu, Cao Fengyan, Xie Haifeng, Zhang Mian, Gong Yanqing, Zhang Chaofeng
(L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China.
(L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China
J Pharmacol Exp Ther. 2017 May;361(2):268-279. doi: 10.1124/jpet.116.239137. Epub 2017 Mar 9.
Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, and eventually most patients develop respiratory failure with a median survival rate of 2 to 3 years after diagnosis due to the lack of clinically effective therapies. Mogroside IIIE (MGIIIE), a cucurbitane-type compound, was isolated from MGIIIE has shown the strongest inhibition of nitric oxide release, a crucial inflammatory factor, from lipopolysaccharide (LPS)-treated RAW264.7 cells compared with other mogrosides. In the pulmonary fibrosis mouse model induced by bleomycin, MGIIIE treatment attenuated pulmonary fibrosis, indicated as a reduction in myeloperoxidase activity, collagen deposition, and pathologic score. MGIIIE also significantly suppressed expression of several important fibrotic markers, e.g., -smooth muscle actin, collagen I, transforming growth factor- (TGF-) signal, and metalloproteinases-9/tissue inhibitor of metalloproteinase-1. Furthermore, MGIIIE blocked tansdifferentiation of lung resident fibroblasts into myofibroblast-like cells induced by TGF- or LPS and subsequently inhibited collagen production in lung fibroblasts. These data indicate that MGIIIE is a potent inhibitor for pulmonary fibrosis. In vitro and in vivo mechanistic studies have shown that MGIIIE significantly decreased expression of toll-like receptor 4 (TLR4) and its downstream signals of myeloid differentiation factor 88 (MyD88)/mitogen-activated protein kinase (MAPK), an inflammatory signal essential for extracellular matrix (ECM) deposition in pulmonary fibroblasts. Taken together, these results demonstrate that MGIIIE significantly prevents pulmonary fibrosis by inhibiting pulmonary inflammation and ECM deposition through regulating TLR4/MyD88-MAPK signaling. Our study suggests that MGIIIE may have therapeutic potential for treating pulmonary fibrosis in clinical settings.
特发性肺纤维化是一种进行性纤维化性肺病，由于缺乏临床有效治疗方法，最终大多数患者会发展为呼吸衰竭，诊断后的中位生存期为2至3年。罗汉果甜苷IIIE（MGIIIE）是一种葫芦烷型化合物，从罗汉果甜苷IIIE中分离得到，与其他罗汉果甜苷相比，它对脂多糖（LPS）处理的RAW264.7细胞中关键炎症因子一氧化氮的释放具有最强的抑制作用。在博来霉素诱导的肺纤维化小鼠模型中，MGIIIE治疗减轻了肺纤维化，表现为髓过氧化物酶活性、胶原蛋白沉积和病理评分降低。MGIIIE还显著抑制了几种重要纤维化标志物的表达，例如α-平滑肌肌动蛋白、I型胶原蛋白、转化生长因子-β（TGF-β）信号以及金属蛋白酶-9/金属蛋白酶组织抑制剂-1。此外，MGIIIE阻断了由TGF-β或LPS诱导的肺驻留成纤维细胞向肌成纤维细胞样细胞的转分化，并随后抑制了肺成纤维细胞中的胶原蛋白产生。这些数据表明MGIIIE是一种有效的肺纤维化抑制剂。体外和体内机制研究表明，MGIIIE显著降低了Toll样受体4（TLR4）及其下游髓样分化因子88（MyD88）/丝裂原活化蛋白激酶（MAPK）信号的表达，这是肺成纤维细胞中细胞外基质（ECM）沉积所必需的炎症信号。综上所述，这些结果表明MGIIIE通过调节TLR4/MyD88-MAPK信号抑制肺部炎症和ECM沉积，从而显著预防肺纤维化。我们的研究表明，MGIIIE在临床环境中可能具有治疗肺纤维化的潜力。
