Abstract: Objective To analyze the relationship between endothelial function-related biomarkersin serum of asthmatic children and the prognosis of asthma,so as to provide evidence for the assessment of asthma prognosis. Methods A total of 89 asthmatic patients aged 5-14 years in Changzhou Children's Hospital Affiliated to Nantong University were enrolled in this study from October 2016 to December 2017,and meanwhile 92 healthy children were selected in control group.Serum samples of the participants were collected for measurement of concentrations of vascular endothelial growth factor(VEGF),periostin,adiponectin(APN),leptin and inducible nitric oxide synthase(iNOS) activity using ELISA and other commercial kits.Serum concentrations of L-arginine,asymmetric dimethylarginine(ADMA) and symmetric dimethylarginine(SDMA) were measured by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Children were followed up for one year,and the number of wheezing occurred in this period was recorded.Data were analyzed by orthogonal partial least squares-discriminant analysis(OPLS-DA) in order to screen endothelial function-related biomarkers that showed crucial influence on the prognosis of asthma. Results Serum levels of arginase I(Arg I),periostin,VEGF and leptin as well as iNOS activity significantly increased in asthmatic children,while L-arginine content decreased in children with asthma(P<0.05).The OPLS-DA model showed that asthma group and control group could be distinguished based on endothelial function-related multi-markers.The variable importance factor(VIP) values of Arg I,iNOS activity and VEGF were 2.11,1.23 and 1.09,respectively,indicating them as key endothelial function-related biomarkers for distinguishing asthma children from control group.Finally 70 children finished one-year follow-up.Compared with non-recurrent wheezing group(n=43),recurrent wheezing group(n=27) had increasing levels of serum ADMA and Arg I,as well as decreasing levels of periostin and APN(P＜0.05).Both S-plot and VIP values of the OPLS-DA model indicated that APN,periostin,and Arg I were key endothelial function-related markers that could distinguish the two groups. Conclusions The homeostasis of vascular endothelial function-related markers is disrupted in the circulation of asthmatic children.APN,POSTN and Arg I have good predictive value for the prognosis of asthma in children.

Key words: asthma, endothelial function, periostin, arginase I

摘要： 目的 分析哮喘儿童血清中血管内皮功能相关标记物的变化情况及其与疾病预后的关系,为儿童哮喘预后的评估提供依据。方法 收集2016年10月-2017年12月在南通大学附属常州儿童医院就诊的89例5～14岁哮喘患儿在哮喘发作期的血清样本和92例健康儿童的血清样本,运用ELISA和其他商用测试盒检测其中内皮功能相关标志物血管内皮生长因子(VEGF)、精氨酸酶I(Arg I)、骨膜蛋白(POSTN)、脂联素(APN)和瘦素的浓度以及诱导型一氧化氮合酶(iNOS)活性,并用高效液相串联质谱(HPLC-MS/MS)检测L-精氨酸、甲基化精氨酸ADMA和SDMA的浓度。此后对哮喘组患儿进行为期1年的随访,记录在此期间出现喘息发作的次数。运用正交偏最小二乘法-判别分析(OPLS-DA)分析数据,筛选对哮喘疾病预后有关键影响的血管内皮功能相关标记物。结果 哮喘组儿童血清中Arg I、POSTN、VEGF和瘦素的含量显著增加,iNOS活性显著增高,L-精氨酸浓度显著下降(P<0.05)。OPLS-DA模型显示,基于内皮功能多标记物哮喘组可以和对照组显著区分,且Arg I、iNOS活性以及VEGF水平的变量重要性因子(VIP)值分别为2.11、1.23、1.09,是区分哮喘组和对照组的关键内皮标记物。随访后1年,随访成功70例,其中反复喘息组(n=27)与非反复喘息组(n=43)相比,血清ADMA和Arg I的含量显著增加,POSTN和APN含量显著减少(P<0.05)。OPLS-DA模型的S-plot图和VIP值排序都表明区分两组的关键内皮标记物是APN、POSTN和Arg I。结论 哮喘儿童血清中多种内皮功能相关的生物标记物稳态失衡,其中APN、POSTN和Arg I对儿童哮喘的疾病预后有较高的预测价值。

关键词: 哮喘, 血管内皮功能, 骨膜蛋白, 精氨酸酶I