内皮抑素通过Notch1/血小板源生长因子信号通路对小鼠肺纤维化的抑制作用  

Inhibitory effect of endostatin on pulmonary fibrosis in mice through Notch1/platelet-derived growth factor signaling pathway

作　　者：谢晗 陈琼[2] 王懿春[2] Xie Han;Chen Qiong;Wang Yichun(School of Medicine,University of South China,Hengyang 421001,China;Department of Critical Care Medicine,Hunan Cancer Hospital,Changsha 410013,China)

机构地区：[1]南华大学医学院,湖南衡阳421001 [2]湖南省肿瘤医院重症医学科,长沙410013

出　　处：《中华危重症医学杂志（电子版）》2019年第6期361-366,共6页Chinese Journal of Critical Care Medicine:Electronic Edition

基　　金：湖南省自然科学基金项目(2018JJ2245);湖南省临床医疗技术创新引导计划项目(2017sk50607)

摘　　要：目的研究内皮抑素通过Notch1/血小板源生长因子(Notch1/PDGF)信号通路对小鼠肺纤维化的抑制作用。方法将30只小鼠分为对照组、模型组和内皮抑素组,每组各10只。模型组和内皮抑素组小鼠给予气管内注射博莱霉素(5 mg/kg)以建立肺纤维化模型,对照组小鼠仅注射等量等渗NaCl溶液;内皮抑素组小鼠每天腹腔注射内皮抑素(2.3 mg/kg),对照组和模型组小鼠每天腹腔注射等量等渗NaCl溶液,所有小鼠均持续注射21 d。21 d后处死所有小鼠,取左肺组织行病理学染色;取右肺组织,应用Western-blotting法检测Collagen I,Notch1/PDGF信号通路相关蛋白转化生长因子β1(TGF-β1)、Hes1、Hey1、PDGF-B、PDGF受体β(PDGFR-β)及周细胞相关蛋白Desmin、神经元-胶质细胞抗原2(NG2)及α-平滑肌肌动蛋白(α-SMA)的表达水平。结果光镜下,可见对照组小鼠肺泡结构完整,未见异常胶原蛋白;模型组小鼠肺泡结构被破坏,有大量胶原蛋白沉积;内皮抑素组小鼠可见肺组织结构相对完整,而胶原蛋白明显减少。3组小鼠间Collagen I、TGF-β1、Hes1、Hey1、PDGF-B、PDGFR-β、Desmin、NG2及α-SMA蛋白表达水平的比较,差异均有统计学意义(F=12.068、30.603、29.757、35.451、16.059、16.420、24.512、19.084、28.102,P均<0.001)。进一步两两比较发现,内皮抑素组小鼠的Collagen I、TGF-β1、Hes1、Hey1、PDGF-B、PDGFR-β及α-SMA蛋白表达水平均显著低于模型组小鼠,Desmin及NG2蛋白表达水平均显著高于模型组小鼠(P均<0.05);而内皮抑素组与对照组小鼠间Collagen I、TGF-β1、Hes1、Hey1、PDGF-B、PDGFR-β、Desmin、NG2及α-SMA蛋白表达水平的比较,差异均无统计学意义(P均>0.05)。结论内皮抑素可通过Notch1/PDGF信号通路抑制周细胞向肌成纤维细胞转化,从而影响小鼠肺纤维化。Objective To investigate the inhibitory effect of endostatin on pulmonary fibrosis in mice via the Notch1/platelet-derived growth factor(PDGF)signaling pathway.Methods A total of 30 mice were randomly divided into a control group,a model group and an endostatin group,with 10 mice in each group.Mice in the model and endostatin groups were given bleomycin(5 mg/kg)by intratracheal injection to establish a model of pulmonary fibrosis,and mice in the control group were injected with equal volume of isotonic NaCl solution.Then,mice in the endostatin group were given endostatin(2.3 mg/kg)daily,and mice in the control and model groups were injected with equal volume of isotonic NaCl solution,all by intraperitoneal injection for 21 days;afterwards,all mice were sacrificed.The left lung tissue was taken for pathological staining,and the right lung tissue was used to detect expression levels of Collagen I,Notch1/PDGF signaling pathway-related proteins[transforming growth factor-beta 1(TGF-β1),Hes1,Hey1,PDGF-B,PDGF receptor-beta(PDGFR-β)],and pericyte proteins[Desmin,neuron-glial antigen 2(NG2),alpha-smooth muscle actin(α-SMA)]by Western-blotting.Results Under light microscope,the alveolar structure was intact and no abnormal collagen was found in the control group;the alveolar structure was destroyed and massive collagen was deposited in the model group;the alveolar structure was relatively intact and collagen significantly reduced in the endostatin group.The expression levels of Collagen I,TGF-β1,Hes1,Hey1,PDGF-B,PDGFR-β,Desmin,NG2 andα-SMA were significantly different among three groups(F=12.068,30.603,29.757,35.451,16.059,16.420,24.512,19.084,28.102;all P<0.001).Meanwhile,compared with the model group,the expression levels of Collagen I,TGF-β1,Hes1,Hey1,PDGF-B,PDGFR-βandα-SMA were much lower and the expression levels of Desmin and NG2 were much higher in the endostatin group(all P<0.05).However,the expression levels of Collagen I,TGF-β1,Hes1,Hey1,PDGF-B,PDGFR-β,Desmin,NG2 andα-SMA showed no significant differ

关 键 词：肺纤维化 内皮抑素类 NOTCH1 血小板源生长因子 小鼠 

分 类 号：R563.9[医药卫生—呼吸系统]