COPD合并肺源性心脏病患者血清ICOS、ICOSL水平变化及临床意义.pdf

282疑难病杂志 2 0 2 4年3月第2 3卷第3期Chin J Diffic and Compl Cas,March2024,Vol.23,No.3D01】10.396 9/j.i s s n,16 7 1-6 450.2 0 2 4.0 3.0 0 5COPD合并肺源性心脏病患者血清ICOS、ICOSL水平变化及临床意义心血管疾病专题钱王燕，虞鸣娟，陈访，李妍妍，张赛，葛小宁，陈润祥基金项目：江苏省卫生健康委科研课题（BJ22074)作者单位：2 150 0 0 上海交通大学医学院苏州九龙医院检验科（钱王燕、虞鸣娟、陈访、李妍妍），心内科（张赛、葛小宁、陈润祥）通信作者：虞鸣娟，E-mail：4352 338 44 q q.c o m【摘要】目的观察慢性阻塞性肺疾病(COPD)合并肺源性心脏病(PHD)患者血清诱导性共刺激分子（I C O S）和诱导性共刺激分子配体（ICOSL）水平变化及临床意义。方法选择2 0 2 0 年6 月一2 0 2 3年2 月上海交通大学医学院苏州九龙医院心内科收治COPD患者17 2 例，根据患者是否合并PHD分为合并PHD组8 2 例和COPD组90例。根据肺动脉收缩压(PASP)将PHD患者分为轻度亚组(30 50 mmHg,21例）、中度亚组(51 7 0 mmHg,37例）和重度亚组(7 1 mmHg,24 例),再根据纽约心脏病协会(NYHA)分级将 PHD 患者分为 I 级亚组(44 例）、I V级亚组(38 例）。酶联免疫吸附试验检测血清ICOS、I CO SL水平，分析ICOS、I CO SL与PASP、NYH A 分级之间的相关性，受试者工作特征(ROC）曲线分析ICOS、I CO SL诊断COPD合并PHD的价值。结果合并PHD组血清ICOS、ICOSL水平高于COPD组（t=14.526、34.50 8，P均 0.0 0 1）。重度亚组血清ICOS、I CO SL及PASP水平高于中度亚组和轻度亚组（F/P=125.351/0.001、16 3.591/0.0 0 1、8 4.2 92/0.0 0 1），I V 级亚组血清ICOS、I C 0 SL水平均高于II级亚组(t/P=11.658/0.001、2 7.345/0.0 0 1)。PH D 患者血清ICOS、I CO SL水平与PASP、NYH A 分级均呈正相关（r=0.439、0.416、0.50 1、0.497，P均 0.0 0 1）。血清ICOS、I CO SL及二者诊断COPD患者合并PHD的曲线下面积分别为0.7 8 0.0.7 2 3、0.92 6，二者联合高于单独ICOS、I CO SL诊断（Z=4.021、5.194,P均 0.0 0 1）。结论COPD合并PHD患者血清 ICOS、I CO SL水平显著增高,且与肺动脉高压以及心功能降低有关,联合检测 ICOS、I CO SL可有效评估 COPD患者 PHD 风险。【关键词】慢性阻塞性肺疾病;肺源性心脏病；肺动脉高压；诱导性共刺激分子；诱导性共刺激分子配体【中图分类号】R563.3;R541.5Changes in serum ICOS and ICOSL levels and clinical significance in patients with COPD combined with pulmonaryheart disease Qian Wangyan,Yu Mingjuan,Chen Fang,Li Yanyan,Zhang Sai,Ge Xiaoning,Chen Runxiang.*Depart-ment of Laboratory Medicine,Suzhou Jiulong Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai215000,ChinaFunding program:Jiangsu Provincial Health and Wellness Commission Scientific Research Project(BJ22074)Corresponding author:Yu Mingjuan,E-mail:435233844 Abstract Objective To observe the changes of serum levels of inducible co-stimulatory molecules(ICOS)andinducible co-stimulatory molecule ligands(ICOSL)and clinical significance in patients with chronic obstructive pulmonarydisease(COPD)combined with pulmonary heart disease(PHD).Methods One hundred and seventy-two COPD patientsadmitted to the Department of Cardiology,Suzhou Jiulong Hospital,School of Medicine,Shanghai Jiaotong University,fromJune 2020 to February 2023 were selected and divided into the PHD group(82 patients)and the COPD group(90 patients)according to whether they were combined with PHD or not.PHD patients were divided into mild subgroups(30-50 mmHg,21 cases),moderate subgroups(51-70 mmHg,37 cases),and severe subgroups(71 mmHg,24 cases)according to pulmo-nary artery systolic pressure(PASP),and then PHD patients were divided into subgroups of grades I to II(44 cases),andgrades II to IV(38 cases)according to the New York Heart Association(NYHA)classification.Enzyme-linked immunosor-bent assay(ELISA)was used to detect serum ICOS and ICOSL levels and analyze the correlation between ICOS,ICOSL andPASP,NYHA classification,and the value of ICOS and ICOSL in diagnosing COPD combined with PHD was analyzed bythe subjects work characteristics(ROC)curve.Results The serum ICOS and ICOSL levels in the PHD group were higherthan those in the COPD group(t=14526,34.508,P0.001).Serum ICOS and ICOSL levels were higher in the severe sub-group than in the moderate and mild subgroups(F/P=125.351/0.001,163.591/0.001,84.292/0.001),and serum ICS【文献标识码】A疑难病杂志 2 0 2 4 年3月第2 3卷第3期Chin J Dific and Compl Cas,March 2024,Vol.23,No.3was higher in the subgroups of grade II-IV,ICOSL levels were higher than those in the subgroups of grades I-II(t/P=11.658/0.001,27345/0.001).The serum ICOS and ICOSL levels of patients with PHD were positively correlated with thePASP and NYHA grading(r=0.439,20416,0.501,0.497,P0.001).ICOS,ICOSL and both the area under the curve of com-bined PHD in patients with COPD diagnosis was 0.780,0.723,0.926,respectively,and the combination of the two was higherthan the diagnosis of ICOS and ICOSL alone(Z=4.021,5.194,and P all 0.05），具有可比性。本研究已经获得医院伦理委员会批准（伦审2 0 2 0 32号），患者或家属知情同意并签署知情同意书。1.2病例选择标准PHD 诊断标准参考内科学中283.相关诊断标准5。（1)纳入标准:符合慢性阻塞性肺疾病诊治指南(2 0 13年修订版)诊断标准6 ;年龄18 岁以上。（2)排除标准：闭塞性细支气管炎、肺结核、肺间质纤维化、支气管扩张、支气管哮喘患者；先天性心脏病、冠心病、瓣膜性心脏病和心肌病;肺动脉高压、左心疾病、慢性血栓栓塞和其他引起肺动脉高压的疾病；肺动脉瓣或右室流出道的狭窄；合并血液病、肝病、肾病和肿瘤的患者。1.3观测指标与方法1.3.1肺动脉高压、心功能分级评估标准：患者平卧，以EPIQ7C超声诊断仪（荷兰飞利浦公司）,X5-1探头频率为2.5 4.0 MHz,脉冲多普勒或连续多普勒测量三尖瓣反流速度，根据多普勒公式获得右房与右室间收缩期最大压力差（跨瓣压差），跨瓣压差+右房压=心脏超声测量肺动脉收缩压（PASP）。根据PASP将PHD患者分为轻度亚组（30 50 mmHg,21例）、中度亚组(51 7 0 mmHg,37 例)和重度亚组(7 1 mmHg,24例7 。根据NYHA分级8 将PHD患者分为I级亚组(44 例）、I V级亚组(38 例)。1.3.2血清ICOS、I CO SL检测：COPD患者人组后次日晨均采集静脉血3ml注人真空试管，室温下静置约60min,取上层液离心留取上清液-8 0 保存。以VarioskanLUX酶标仪（美国赛默飞公司），采用酶联免疫吸附试验检测血清ICOS、I CO SL水平,ICOS试剂盒购自上海信裕生物科技有限公司，ICOSL试剂盒购自上海抚生实业有限公司。1.4统计学方法采用SPSS25.00软件进行数据分析。计量资料经Kolmogorov-Smirnov法检验符合正态分布以（s）表示，组间比较采用单因素方差分析（两两对比采用LSD-t检验）或独立样本t检验；计数资料以频数或率（%）表示，比较采用x检验；Pearson或Spearman分析血清ICOS、I CO SL与PASP、NYH A 分级的相关性；受试者工作特征曲线（ROC)分析ICOS、ICOSL单独及联合诊断COPD合并PHD的价值。P2840.05为差异有统计学意义。2结果2.12组血清ICOS、I CO SL水平比较合并PHD组血清 ICOS、I CO SL水平高于 COPD组(P 中度亚组 轻度亚组(P均 0.0 1)，见表2。表2 不同肺动脉高压程度PHD患者血清 ICOS、I CO SL水平及PASP比较(s)Tab.2 Comparison of serum ICOS and ICOSL levels and PASP inpatients with PHD with dfferent degrees of pulmonary hy-pertension组别例数ICOS(ng/L)轻度亚组21中度亚组37315.47 50.24重度亚组24342.86 32.46F值125.351P值0.0012.3不同心功能分级PHD患者血清ICOS、I CO SL水平比较血清ICOS、I CO SL水平比较，I V级亚组均高于I级亚组(P0.01),见表3。表3不同心功能分级PHD患者血清 ICOS、I CO SL水平比较(s,ng/L)Tab.3Comparison of serum ICOS and ICOSL levels in patientswith PHD with different cardiac function classifications组别例数I I级亚组44 I V级亚组38值P值2.4血清ICOS、I CO SL水平与PASP、NYH A 分级的相关性PHD患者血清ICOS、I CO SL水平与PASP、NYHA分级均呈正相关(P0.01），见表4。疑难病杂志2 0 2 4年3月第2 3卷第3期Chin JDiffic and Compl Cas,March2024,Vol.23,No.3PHD患者血清ICOS、I CO SL水平与PASP、NYH A 分级的相关性Tab.4Correlation of serum ICOS and ICOSL levels with PASPand NYHA classification in patients with PHDICOSL项目值P值PASP0.439NYHA分级0.4162.5血清ICOS、I CO SL诊断COPD患者合并PHD的ICOSICOSL309.42 82.735 213.26 756.47172.35 32.692 432.51 106.7114.52634.5080.0010.001ICOSL(ng/L)PASP(mmHg)260.54 20.544635.12128.5740.25 5.195 296.87 352.6862.35 8.125 590.23 106.4982.35 9.05163.5910.001ICOS279.35 23.81344.24 26.5911.6580.001表4F价值分析绘制ICOS、I CO SL诊断COPD患者合并PHD的价值ROC曲线，并计算曲线下面积（AUC），结果显示：血清ICOS、I CO SL及二者联合诊断COPD患者合并PHD价值的AUC分别为0.7 8 0、0.7 2 3、0.92 6，二者联合优于各自单独预测效能（Z=4.021、5.194，P均 0.0 0 1),见表5和图1。表5血清ICOS、I CO SL诊断COPD患者合并PHD的效能Tab.5Efficacy of ICOS and ICOSL in diagnosing combined PHDin COPD patients约登因素临界值ICOS237.65 ng/L0.788(0.719 0.846)ICOSL3 965.08 ng/L 0.723(0.650 0.788)二者联合0.926(0.876 0.961)1.0F84.2920.80.0010.60.40.20图11血清 ICOS、I CO SL诊断COPD患者合并PHD的ROC图ICOSLFig.1ROC plot of combined PHD in patients with COPD diag-4 935.27 101.45nosed by ICOS and ICOSL5.535.14 96.2027.3450.001ICOS0.0010.001AUC(95%CI)0.20.40.61-特异度3讨论目前的研究结果显示COPD是PHD 的主要病因，约占8 7%9,肺动脉高压是COPD演变为PHD的关键因素,持续的慢性缺氧引起内皮型一氧化氮合酶和前列环素合酶表达下调,内皮素-1合成增加,导致肺血值P值0.5010.0010.4970.001敏感度特异度指数0.7560.7770.5330.7320.7550.4870.9510.8890.840ICOSICOSL二者联合参考线0.81.0疑难病杂志 2 0 2 4 年3月第2 3卷第3期Chin J Dific and Compl Cas,March 2024,Vol.23,No.3管异常收缩和肺动脉高压，长期肺动脉高压影响下肺动脉平滑肌增生,纤维肌内膜增厚,发生肺血管重塑,肺血管阻力增加,继而引起右心室代偿性肥厚和扩张,随着病情的发展右心室逐渐发生失代偿,最终引起PHD10。研究显示免疫炎性反应可驱动内皮损伤、血管张力调节受损和增殖性血管病变,与肺动脉高压密切相关1,肺动脉高压患者和动物模型肺血管均可观察到不同程度的血管周围炎性细胞浸润，包括T淋巴细胞、B淋巴细胞、巨噬细胞、树突状细胞和肥大细胞,肺动脉高压患者外周血中也可检测到炎性细胞因子水平升高,表明免疫炎性反应可能参与肺动脉高压的病理过程12 1。ICOS 是一种 T细胞受体,在 T细胞活化后表达上调,与其配体ICOSL结合调节免疫反应,对 T细胞增殖分化、细胞因子的产生和T细胞依赖的B细胞反应至关重要13。在T细胞增殖分化方面,ICOS介导T细胞共刺激导致效应细胞因子如IL-4和 IL-10的产生,也可小幅度刺激IL-2、干扰素（IFN)-和肿瘤坏死因子(TNF)-的产生,在辅助性T细胞（Th)2应答中发挥比Thl应答更重要的作用。ICOS还影响滤泡辅助性T细胞、Th17 细胞和调节性 T细胞的扩增,阻断ICOS可抑制Th17分化,减轻炎性反应14。ICOSL作为ICOS的配体，广泛表达于树突细胞、巨噬细胞、B淋巴细胞、成纤维细胞、上皮细胞和血管内皮细胞等多种类型细胞中，在抗原应答过程中诱导和传递ICOS介导的T细胞共刺激信号,增强细胞因子IL-10和IL-23分泌、I类MHC的抗原交叉呈递、树突细胞与内皮细胞的黏附以及趋化因子的迁移功能，还可促使内皮细胞与多形核白细胞之间黏附13本研究发现合并PHD组血清ICOS、I CO SL水平增高,且随着肺动脉高压和心功能分级的增加而增加，表明两者可能也参与COPD向PHD的进展过程。ICOS、I CO SL表达改变可导致免疫功能障碍，与自身免疫性疾病、恶性肿瘤、肝肺疾病等有关,研究显示多发性骨髓瘤患者外周血中sICOS 和 sICOSL水平升高,并且与肿瘤负荷增加,Durie-Salmon 晚分期,总生存率低下相关15。在哮喘小鼠模型中，先天淋巴样细胞（I LC2)表面表达的ICOSL与调节性T细胞（Treg）表面表达的ICOS相互结合和作用调节Treg-ILC2间平衡,ICOS过表达可促使ILC2活化，诱导Th2型免疫反应和哮喘16 。CD8*T淋巴细胞通过ICOS/ICOSL介导的信号传导，修复急性肝损伤组织，促使肝脏愈合1。ICOS/ICOSL免疫调节轴还参与肺结节病的活动和消退过程，与健康人群相比,肺结节病患者外周血单核细胞中ICOSL表达显著升高18 。ICOS、I CO SL参285.与COPD合并肺源性心脏病的机制尚不清楚,推测ICOS/ICOSL轴激活可能通过促使肺动脉高压导致COPD患者发生PHD。首先，ICOS过表达导致促炎（I FN-、I L-17）和促纤维化（IL4）细胞因子合成，引起成纤维细胞活化增殖和细胞外基质合成增加192 0 1,导致肺血管纤维化和重塑，促使肺动脉高压形成。其次，表达ICOS的T细胞直接与表达ICOSL的内皮细胞相互作用，促使血管炎性细胞浸润，引起血管内皮损伤和功能障碍，另外在氧化和炎性反应等应激刺激下ICOS/ICOSL通路被激活，上调内皮细胞上ICOS、ICOSL表达,从而引起T细胞炎性反应和血管内皮功能障碍2 1,继而发生血管张力调节受损和增殖性血管病变,并最终发展为肺动脉高压和PHD。ROC曲线分析显示血清ICOS、I CO SL对于诊断COPD发生PHD具有较高的价值，表明检测血清ICOS、I C O SL水平可鉴别COPD合并PHD的风险，联合ICOS、I CO SL后诊断效能明显提高，提示临床可通过检测血清ICOS、I CO SL的变化识别PHD高危患者。综上所述,COPD合并PHD患者血清ICOS、I C O SL水平显著增高,且与肺动脉高压以及心功能分级增加有关,联合检测血清ICOS、I C O SL水平可评估COPD患者肺动脉高压严重程度和心功能减退情况，识别COPD患者发生PHD风险。ICOS、I C O SL可能在PHD的发展中具有致病作用。利益冲突：所有作者声明无利益冲突作者贡献声明钱王燕：设计研究方案，实施研究过程，论文撰写；虞鸣娟：提出研究思路，论文审核；陈访：实施研究过程，资料搜集整理；李妍妍：实施研究过程，参与撰写；张赛：进行统计学分析；葛小宁：实施研究过程，数据分析整理；陈润祥：论文修改参考文献1 You L,Niu H,Huang 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