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. 2020 Jul 20;40(7):1062–1065,封三页. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2020.07.23

生物标志物在特发性肺纤维化中的临床价值

Clinical value of biomarkers in diagnosis and treatment of idiopathic pulmonary fibrosis

Yubin FAN 1, Rongling HE 1, Lijun ZOU 1, Jie MENG 1,*
PMCID: PMC7386223  PMID: 32895164

Abstract

特发性肺纤维化（IPF）以成纤维细胞灶进行性积聚和肺泡结构破坏为特点的慢性间质性肺炎。由于发病和进展机制未完全阐明，目前缺乏有效的早期筛查和治愈方法，患者总体预后差，中位生存期仅2~4年。近年，多篇研究证实数十种参与IPF发展过程的分子可作为潜在生物标志物。这些生物标志物可以在IPF的早期诊断（如SP-D、MMP-7、骨桥蛋白）、判断预后（如端粒酶长度、KL-6、mtDNA、HSP-70、LOXL2、CXCL13、miRNA、ICAM-1、CCL18）、指导治疗（如TOLLIP rs3750920基因型、SAMS评分、SP-D）、提供新的治疗靶点（如TERT、TERC、RTEC、PARN）等方面发挥重要作用。

Keywords: 特发性肺纤维化, 生物标志物, 预后, 诊断

特发性肺纤维化（IPF）是以不明原因的成纤维细胞灶进行性聚集和肺泡结构破坏为特点的慢性间质性肺炎，主要在老年发病，在75岁以上的人群中患病率达0.63‰[1]，临床上多表现为进行性呼吸困难伴刺激性干咳，患者多死于呼吸衰竭和继发性肺部感染。由于本病的发病和进展机制未完全阐明，临床症状缺乏特异性，大部分患者在肺功能渐进性下降数年才得以确诊，约14%的患者在1年内出现急性加重[2]，其中60%在1月内死亡[3]，病程稳定者中位生存期也在2~4年[4]。目前已上市的吡非尼酮和尼达尼布可以延缓肺纤维化，且尼达尼布可有效预防急性加重及减低死亡率风险[5]，此外还有新药如氟非尼酮在研发中[6-7]。因此，IPF患者的早期精准诊断、预后及疗效评估非常重要。由于IPF的高度异质性，且临床表现无特异性，早期诊断、开始治疗时机、方案调整、预后及疗效评估存在一定困难，需要简单安全且有明确意义的IPF生物标志物来协助。

1. IPF疾病的诊治现状

IPF的诊断需在排除其他已知ILD的基础上，HRCT表现为普通型间质性肺炎（UIP）或HRCT与外科肺活检（SLB）病理类型符合特定的组合[8]。而仅有53.4%患者表现为UIP[9]，且HRCT以UIP诊断IPF敏感性仅78.5%[10]。SLB虽为获取肺组织金标准，但手术相关病死率可高达16%[11]。当影像学表现与组织病理学表现不一致时，诊断就需要多学科讨论协助。但多学科讨论中需要多个的临床经验丰富相关专科医生，并非所有医院都具备，因此不能及时诊断和治疗。性别-年龄-生理学（GAP）模型可用于预测IPF死亡风险[12]，但由于IPF患者个体预后差异大、病史难以获得，该模型在临床管理中的作用有限。

2. 生物标志物

生物标志物是指可以评估生理过程、病理过程及治疗的药理学反应的客观测量指标，无论是体内实验和体外实验，还是临床试验的早期疗效和安全性评估中都具有极大价值[13]。呼吸系统疾病的生物标志物包括肺组织、支气管肺泡灌洗液和血液中的生化分子以及遗传多态性的检测，广义上还包括关于影像学和肺功能的测定。生物标记物来源广泛，其中以血液标本最为方便。

3. 生物标志物在IPF中的应用价值

3.1. 了解易感性

在IPF患者中，TOLLIP水平下降，这或许与其编码基因的单核苷酸多态性（rs111521887，rs5743894，rs5743890）相关，其中TOLLIP多态性rs3750920（TT基因型）会下调TOLLIP，致炎症纤维化[14]，而TOLLIP rs5743890突变者IPF的易感性低[15]。MUC5B基因rs3570595单核苷酸多态性也可增加IPF易感性，其在IPF患者中占38%，对照组占9%[16]。对于存在易感性的正常人，可建议其尽量避免IPF相关高危因素（如吸烟、粉尘、胃食管返流等），尽早预防。

3.2. 协助诊断

IPF的诊断是一种排它性诊断，需与其他已知类型ILD相互鉴别。血清中的表面活性蛋白-D（SP-D） > 31 ng/mL、血清基质金属蛋白酶-7（MMP-7） > 1.75 mg/mL和骨桥蛋白 > 6 ng/mL可分别作为鉴别IPF与其他ILD的生物标志物，其中SP-D、MMP-7、骨桥蛋白的敏感性和特异性分别为70%和65%，35%和91%，71%和63%[17]。这可能需要三者联合诊断，以提高诊断正确率。

3.3. 评估预后

3.3.1. 生存率与死亡率

IPF患者血液中的端粒长度与同龄人相比缩短，端粒更短的IPF患者的生存率更差，是独立于性别、年龄、用力肺活量、DLCO%之外的危险因素[18]。端粒酶突变可导致端粒变短，IPF患者端粒相关基因存在四种突变型：端粒酶逆转录酶（TERT）、人端粒酶RNA元件（TERC）、端粒长度调节酶（RTEC）、聚腺苷酸特异性核糖核酸酶(PARN)。这四种突变比组织病理学表现更能预测疾病的加速进展过程，但各种突变型之间生存率没有差异[19]。在CLIA认证的实验室中，端粒酶长度检测费用比许多中心的常规肺功能检查便宜[20]。此外部分患者无法配合肺功能检查，因此端粒酶长度检测可能是一个不错的选择。

KL-6属MUC1粘蛋白，是AECⅡ增殖和损伤的生物标志物。血清KL-6初始水平 > 1000 U/mL的IPF患者的生存率降低[21]，若血清中KL-6继续升高，其生存率进一步降低[22]。因此动态监测血清KL-6的变化可用于评估IPF患者的预后。MMP-7的血清浓度与生存率成负相关，与KL-6联合应用可提高生存预测[23]。

IPF患者血清、肺组织匀浆的线粒体DNA（mtDNA）水平均升高，并与FVC%与DLCO%负相关，当血清mt-ATP6 > 3614.24拷贝数/uL死亡率显著增高[24]。此外，血浆SP-A基线水平每上升49 ng/mL，IPF患者在其上升的第1年的死亡风险增加3.3倍[25]。HSP的自身抗体通过与HSP受体或抗原结合放大炎症效应，IPF患者中HSP-70自身抗体表达多于正常组，且与患者的近期肺功能下降及死亡率相关[26]。除此之外，还有LOXL2等相关生物标志物在研究中[27]。

3.3.2. IPF急性加重（AE-IPF）

据统计AE-IPF每年发病率可高达20%，病死率可高达40%[28]。血清中KL-6 > 1300 U/mL的IPF患者急性加重概率增加[29]。早期AEIPF患者血清中细胞间粘附分子-1（ICAM-1）的水平明显高于稳定期IPF，在稳定IPF患者血清中ICAM-1和KL-6水平正相关，ICAM-1与CRP升高或可作为AE-IPF早期预测指标[14]。IPF患者与正常者血清中miRNA水平存在统计学差异，miR-21、miR-155、miR-199a-5p、miR-200升高，而miR-101-3P、miR-31、let-7a及let-7d降低[30-31]，miR-21、miR-155、miR-101-3P动态变化与IPF的严重程度相关（肺功能FVC，HRCT）[30]，而miR-21和miR-199a-5p在AEIPF患者血清中升高更明显，miR-31和let-7则在AEIPF患者血清中的水平进一步下降[31]。

3.3.3. 肺动脉高压

在IPF中有29%~77%的患者合并肺动脉高压，其死亡风险是无肺动脉高压IPF患者的3倍[32]。虽然右心导管测压为肺动脉高压诊断金标准，但其操作复杂且有创操，存在一定风险。IPF患者血清中的C-X-C基序趋化因子13（CXCL13）水平升高，尤其是并发肺动脉高压患者，但其水平与AEIPF、呼吸衰竭及生存期无明显相关[33]。此外，血清中的趋化因子配体18（CCL18） > 150 ng/mL是IPF者肺动脉高压的独立危险因素，且与与总肺活量，用力肺活量的变化负相关，但不能预测AEIPF[23]。最新研究中IPF患者肺动脉中JAK2，STAT3水平明显升高，且在合并有肺动脉高压者中上调明显[34]，其临床价值需进一步研究。

3.3.4. 指导治疗

IPF自然病程差异大，具有高度异质性，临床上需进一步区分具体亚型，予以个体化的精准治疗，减少药物副作用。N-乙酰半胱氨酸改善TOLLIP rs3750920（TT基因型）患者的病情，但TOLLIP rs3750920（CC基因型）的患者病情则会加重，提示了药物治疗前基因分层分析的重要性[35]。治疗前血清SP-D水平可以预测经吡非尼酮治疗患者的无进展生存期（PFS）及生存率[36]，可为选择药物治疗提供参考依据。胰岛素样生长因子结合蛋白-2和mtDNA在IPF患者血清中升高，经抗纤维化治疗后显著降低[37-38]，提示可作为疗效指标。端粒酶突变IPF患者行肺移植后对药物不良反应敏感性增高，术后严重并发症比率更高[39]。端粒短的IPF患者肺移植术后生存率较差[40]。端粒长度或许可为肺移植及术后药物治疗提供相关帮助。基于52种基因的分子亚表型的评分算法（SAMS）作为生物标志物，将IPF患者分为高风险组和低风险组，两组间有着明显的死亡率和非移植生存率差异，而52基因SAMS的动态升高与%FVC下调、不移植生存率降低有关，SAMS评分动态降低者与抗纤维化治疗相关。GAP指数与52基因的组合可以高准确率的预测预后[41]。

4. 小结

随着对IPF发病机制的进一步理解，多篇研究证实数十种参与IPF上皮细胞损伤与转分化、成纤维细胞增殖和细胞外基质沉积、免疫调节等发展过程的分子可作为潜在生物标志物。这些生物标志物可以客观地反映其病理过程及药物干预的药理反应，不仅可以评估IPF的疾病易感性，还有利于疾病的早期诊断、判断预后以及指导治疗。因此，需要重视特发性肺纤维化相关生物标记物的研究进展。由于IPF疾病的高度异质性、实验方法、随访时间等限制，大部分生物标志物不能排除恶性肿瘤等其他混杂因素来对疾病进行评估，部分生物标志物存在着矛盾的实验结果。但是，大多数研究者对IPF生物标物表示认可，且部分生物标志物（如KL-6）已在IPF患者中广泛开展并取得较好的临床效益。临床需要IPF生物标记物，来对IPF进行分层，以指导用药，达到最大化的疗效及减少药物的副作用，降低医疗费用负担，提供个体化和精准化的治疗。为了挖掘与发现更准确有效的IPF生物标志物需要：多中心队列研究，新的发病机制进展，生物标志物联合检验，生物标志物与临床症状、生理学参数的联合使用。

Biography

范宇斌，硕士，住院医师，E-mail: 178112125@csu.edu.cn

Funding Statement

国家自然科学基金（81470255）

Supported by National Natural Science Foundation of China (81470255)

Contributor Information

范 宇斌 (Yubin FAN), Email: 178112125@csu.edu.cn.

孟 婕 (Jie MENG), Email: mengjie@csu.edu.cn.

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