An excessive accumulation of extracellular matrix composed by insoluble collagen is the core pathogenic change of fibroproliferative diseases including pulmonary fibrosis.We recently found that autophagy,a self-catabolic process that maintains intracellular homeostasis,participates critically in the regulation of collagen degradation in the fibrotic tissues.Here we report that treatment of mice with SB216763,a potent and selective inhibitor of glycogen synthase kinase-3(GSK3),significantly decreased the bleomycin(BLM)-induced acute inflammation,attenuated pulmonary fibrosis,improved the lung function and increased animal survival through activating autophagy.Indeed,we found that treatment of mice or cultured cells with SB216763 restored the autophagy in vivo and in vitro through increasing the expression of autophagy related proteins and decreasing the physical interaction of Bcl-2 and Beclin-1.Additionally,SB216763 stimulated the binding of Bcl-2 and GSK3,which reduces the interaction of Bcl2 and Beclin-1.We conclude that the GSK3 inhibitor SB216763 improves the BLM-induced pulmonary fibrosis through stimulating autophagy core complex to restore the activity of autophagy in fibrotic lung tissue.Our work suggests that using a moderate autophagic agonist,such as SB216763,is a promising therapeutic strategy for the treatment of devastating fibroproliferative diseases such as idiopathic pulmonary fibrosis.
Hong LiuSu MiZhe LiXiaoxi LvKe LiFang HuaZhuowei Hu
探讨蝙蝠蛾被毛孢菌丝体(Mycelium of Hirsutella hepiali Chen et Shen,MHCS)对代谢综合征的影响及作用机制。首先采用游离脂肪酸与MHCS处理肝细胞,检测自噬相关的LC3、p62水平与脂滴堆积。其次高脂喂养小鼠建立代谢综合征模型,将50周龄小鼠随机分为:对照组、模型组、给药组。干预至80周龄后每组随机抽取15只小鼠,测量口服葡萄糖耐量、空腹血糖、胰岛素、胰岛素样生长因子(IGF-1)水平,计算胰岛素抵抗指数(IRI);检测肝脏组织中LC3、p62与炎症相关p-NF-κB p65、NF-κB p65、IL-6与CXCL-8水平;观察肝脏内空泡面积、脂滴堆积与纤维化病理改变;其余小鼠继续饲养至110周龄,统计死亡率。结果表明,MHCS显著上调游离脂肪酸处理的肝细胞自噬水平,给药组小鼠口服葡萄糖耐量、胰岛素抵抗显著改善,自噬水平显著增加,炎症显著缓解,肝脏病理改善且生存率显著增高。提示MHCS可能通过激活肝脏自噬,改善小鼠代谢综合征。
