LPS通过PGE2-EP2信号传导通路诱导肺血管生成  

LPS induces lung angiogenesis via PGE2-EP2 pathway in mouse model

作　　者：张鹏飞[1] 徐晓娅[1] 姜曼[1] 毕玉莉[1] 许继映[1] 韩明勇[1] 

机构地区：[1]山东大学附属省立医院肿瘤中心,山东济南250021

出　　处：《山东大学学报（医学版）》2014年第10期15-19,共5页Journal of Shandong University:Health Sciences

基　　金：国家自然科学基金(81272351);山东省自然科学基金(ZR2012HM020);山东省科技发展计划(2012G0021826)

摘　　要：目的：探讨脂多糖（LPS）诱导肺血管生成的相关信号途径。方法12只6～8周龄的雌性BALB/c小鼠随机分为两组，分别行腹腔注射LPS和PBS，作为LPS组（n＝6）和PBS组（n＝6），建立小鼠炎症模型。采用 HE染色和免疫荧光实验检测肺血管密度，应用ELISA法测定血清血管内皮生长因子（VEGF）。分离正常小鼠肺血管内皮细胞（MPVECs）并培养，分别给予VEGF、PGE2、Celecoxib、EP受体拮抗剂 A H6809和4种 EP受体激动剂（ONO-AE1-259-01、ONO-DI-004、ONO-AE-248、ONO-AE1-329）进行刺激，观察内皮细胞成管情况，检测培养上清液中VEGF表达水平。结果 LPS诱导小鼠肺部炎症反应及血管生成；LPS组小鼠血清VEGF水平明显高于PBS组小鼠（P＜0．01）。单独使用PGE2或VEGF能促进血管生成；Celecoxib可抑制VEGF诱导的肺血管生成，仅EP2受体激动剂 ONO-AE1-259-01能使 MPVECs 上清液中 VEGF 水平升高（P ＜0．05），而 EP2受体拮抗剂A H6809抑制MPVECs培养上清液中的VEGF水平（P＜0．05）。结论 LPS 可以诱导小鼠肺部炎症反应，并使VEGF表达水平升高；Celecoxib可抑制血管内皮细胞VEGF的表达水平。LPS通过PGE2-EP2信号通路介导，促进血管内皮细胞产生VEGF，从而促进血管生成。Objective To investigate the mechanism by which Lipopolysaccharide （LPS）induced angiogenesis in mice lungs.Methods Twelve female BALB/c mice aged 6 to 8 weeks were divided into LPS and PBS groups randomly, which were intraperitoneally injected into LPS and PBS,respectively.Lung tissues were collected to determine the pul-monary blood vessel density by HE staining and C D3 1 immunofluorescence staining.Vascular endothelial growth factor （VEGF）level in serum of all mice were assayed by ELISA.Mouse pulmonary vascular endothelial cells （MPVECs） were stimulated with VEGF,PGE2,Celecoxib,EP receptor inhibitor A H6809 and EP receptor agonists （ONO-AE1-259-01,ONO-DI-004,ONO-AE-248,and ONO-AE1-329）.Then culture supernatant was collected to assay VEGF ex-pression and tube forming test was performed to observe angiogenesis of endothelial cells.Results LPS induced in-flammatory response and angiogenesis in mice lungs.Serum VEGF level of LPS treated mice were higher than those of PBS treated mice （P〈0.01）.VEGF or PGE2 used separately could increase angiogenesis.Celecoxib reduced VEGF levels released by MPVECs and suppressed angiogenesis.VEGF production was increased by ONO-AE1-259-01 （P〈0.05）and decreased by A H6809 （P〈0.05）.Other EP receptor agonists had no significant effects on VEGF produc-tion.Conclusion LPS can induce inflammatory response in mice lungs,and increase serum VEGF level.Celecoxib can counteract this effect.LPS promotes angiogenesis by increasing the production of VEGF via PGE2-EP2 pathway.

关 键 词：脂多糖 PGE2-EP2途径 血管生成 动物模型 

分 类 号：R734.2[医药卫生—肿瘤]