血液生物标志物在慢性阻塞性肺疾病中的研究进展
Advances in Blood Biomarkers in Chronic Obstructive Pulmonary Disease
DOI: 10.12677/md.2024.144065, PDF, HTML, XML,    科研立项经费支持
作者: 贾科良:济宁医学院临床医学院,山东 济宁;韩丽萍*:济宁市第一人民医院呼吸与危重症医学科,山东 济宁
关键词: 慢性阻塞性肺疾病血液生物标志物急性加重期Chronic Obstructive Pulmonary Disease Blood Biomarkers Acute Exacerbations
摘要: 慢性阻塞性肺疾病(Chronic Obstructive Pulmonary Disease, COPD)是一种以气流受限和呼吸困难为特征的慢性炎症性疾病。近年来,血液生物标志物在COPD的诊断、病情评估和治疗监测等方面显示出重要的潜力。血液生物标志物在COPD研究中有许多重要进展,许多研究重点关注了C反应蛋白(C-Reactive Protein, CRP)、白介素-6 (Interleukin-6, IL-6)、肿瘤坏死因子-α (Tumor Necrosis Factor-α, TNF-α)、嗜酸性粒细胞、中性粒细胞与淋巴细胞比值(Nneutrophil-to-Lymphocyte Ratio, NLR)等炎症标志物,以及其他相关标志物如纤维蛋白原、D-二聚体和胱抑素C等。通过总结现有研究成果,可以探讨这些标志物在COPD中的临床应用价值及其在疾病机制研究中的意义,进一步的研究有望揭示更多具有临床意义的生物标志物。
Abstract: Chronic obstructive pulmonary disease is a chronic inflammatory disease characterized by airflow limitation and dyspnea. In recent years, blood biomarkers have shown significant potential in the diagnosis, disease assessment and treatment monitoring of COPD. There have been many important advances in blood biomarkers in COPD research, with many studies focusing on inflammatory markers such as C-reactive protein, interleukin-6, tumor necrosis factor-α, eosinophils, and neutrophil-to-lymphocyte ratio, as well as other related markers such as fibrinogen, D-dimer and cystatin C. By summarizing the existing research results, the clinical application value of these markers in COPD and their significance in the study of disease mechanisms can be explored, and further studies are expected to reveal more biomarkers with clinical significance.
文章引用:贾科良, 韩丽萍. 血液生物标志物在慢性阻塞性肺疾病中的研究进展[J]. 医学诊断, 2024, 14(4): 448-455. https://doi.org/10.12677/md.2024.144065

1. 引言

慢性阻塞性肺疾病(Chronic Obstructive Pulmonary Disease, COPD)是一种常见的呼吸系统疾病,它主要表现为持续存在的呼吸系统症状和气流受限。在慢性阻塞性肺疾病研究领域,寻找和利用生物标志物具有重要意义。一方面这些标志物的变化与炎症过程和肺功能下降有关,为早期诊断提供了重要线索。另一方面,血液生物标志物在预测慢阻肺患者病程及预后方面发挥着关键作用。这些生物标志物的研究不仅有助于更全面地了解COPD的发病机制,还为早期诊断、疾病进展监测提供了有力的支持。本文就血液生物标志物如C反应蛋白(C-Reactive Protein, CRP)、白介素-6 (Interleukin-6, IL-6)、肿瘤坏死因子-α (Tumor Necrosis Factor-α, TNF-α)、嗜酸性粒细胞、中性粒细胞与淋巴细胞比值(Nneutrophil-to-Lymphocyte ratio, NLR)在COPD中的研究进展进行综述。

2. C反应蛋白

C反应蛋白是一种由肝脏产生的急性相蛋白,其水平的升高通常指示有炎症发生。在慢阻肺急性加重期间,C反应蛋白水平显著上升,这反映了体内炎症活性的增加。血清C反应蛋白是COPD稳定期患者急性发作的独立影响因素[1]。C反应蛋白的测定快速且成本低廉,使其成为临床上评估慢阻肺患者炎症状态的常用指标,高水平的CRP与病情加重和预后不良密切相关。Tang等[2]研究指出,慢性阻塞性肺病患者中C反应蛋白的增加会导致患者死亡率升高。随着慢性阻塞性肺病的进展,CRP水平通常呈升高趋势,而患者的营养状况可能会逐渐恶化,这一现象也与患者的预后不良有关。同时,通过C反应蛋白的检测,可以指导急性加重期抗生素的用药剂量,可将抗生素处方用药剂量减少20% [3] [4]

3. 白细胞介素

白细胞介素是一组广泛的细胞因子,调控炎症和免疫反应。在慢阻肺急性加重中,白细胞介素-6和白细胞介素-8的角色尤为重要。Aslani等[5]研究结果显示,慢阻肺患者的IL-6水平明显升高。慢性阻塞性肺疾病的持续性慢性炎症与不良结局有关,并经常导致急性加重的发生。由于IL-6在诱导和维持慢性炎症中起重要作用,因此测量其水平可以预测慢阻肺急性加重的频率,白细胞介素-6的测量值大于14.030 pg/mL是次年慢阻肺急性加重次数增多的危险因素[6]。血清IL-6水平随着慢阻肺的慢性阻塞性肺疾病全球倡议(Global Initiative for Chronic Obstructive Lung Disease, GOLD)分级严重程度的增加而增加[7]。白细胞介素-8主要涉及中性粒细胞的募集和活化。在慢阻肺急性加重期间,IL-8的增加可以促进中性粒细胞迁移到肺部,加重肺组织的炎症和损伤。因此,IL-8常被用作评估慢阻肺加重期间炎症严重程度的生物标志物。细胞因子IL-6和IL-8,在预测疾病进展方面具有独立的预测价值[8]。我国的一项研究表明IL-8等炎症标志物的高水平表达,可用作确定慢性阻塞性肺病急性加重严重程度的标志物[9]。COPD稳定期出院时血清IL-17过表达与一年内急性发作次数有关,对预测一年内急性发作次数有一定价值,入院时IL-17过表达提示频繁急性发作高风险[10]

4. 肿瘤坏死因子α

肿瘤坏死因子α是一种强烈的炎症介质,对于慢阻肺患者的炎症反应具有关键作用。在慢阻肺急性加重期间,TNF-α的表达增加,这与气道炎症、气道重塑和肺功能下降有关。肿瘤坏死因子α在慢阻肺急性加重患者中有重要的临床意义,它是慢阻肺急性加重的重要生物标志物。肿瘤坏死因子α可以参与慢阻肺中全身炎症和气道阻塞的发生,其水平升高与慢阻肺的发生有关[11]。肿瘤坏死因子α不仅加重炎症反应,还可能影响肺组织的结构完整性。在病毒阳性慢阻肺急性加重患者体内有TNF-α参与的全身炎症反应,这是由于病毒诱导的巨噬细胞激活所致。慢阻肺患者的肿瘤坏死因子α水平升高,这表明疾病进展会导致TNF-α水平升高[12]。肿瘤坏死因子α与慢阻肺有关,肿瘤坏死因子α参与气流受限的发生[13]。TNF-α的血浆水平在慢阻肺急性加重发生时会发生变化,并且在恢复过程中落后于其他指标[14]

5. 纤维蛋白原

纤维蛋白原是肝脏生产的一种大分子血浆蛋白,是凝血系统中的关键因子,也是急性期反应蛋白。在慢阻肺患者中,其水平往往增高,这不仅与疾病的急性加重有关,也与长期的预后不良相关。Celli等[15]研究明确指出,慢性阻塞性肺病患者中的纤维蛋白原水平升高与死亡风险的显著增加密切相关。有强有力的证据表明纤维蛋白原与慢阻肺的急性加重以及死亡率增加之间存在关联,纤维蛋白原与疾病严重程度相关,但不能预测肺功能下降,肺功能下降是疾病活动度的替代指标。纤维蛋白原在识别炎症合并症中的作用尚不清楚,在病情稳定的个体中,在病情加重期间口服皮质类固醇药物可减少纤维蛋白原的产生[16]。纤维蛋白原通过促进血栓形成,增加血液粘稠度,可能增加慢阻肺患者发生心血管并发症的风险。与纤维蛋白原 < 4 g/L患者相比,纤维蛋白原水平升高的患者往往炎症反应重,肺气肿、肺炎和动脉粥样硬化的发生率更高。C反应蛋白水平和白细胞计数升高是与慢性阻塞性肺疾病急性加重纤维蛋白原水平升高相关的独立危险因素,纤维蛋白原水平可用于测量慢阻肺急性加重的严重程度[17]。与稳定期的慢阻肺患者相比,慢阻肺急性加重期患者的血浆纤维蛋白原水平升高。此外,纤维蛋白原水平与一些重要功能指标和预后标志物呈正相关,与肺功能呈负相关。血浆纤维蛋白原具有对慢阻肺疾病状态的反应能力,因此有可能成为提示慢阻肺急性加重的重要生物标志物[18]。荟萃分析的研究结果表明,纤维蛋白原水平与慢性阻塞性肺疾病的严重程度之间存在着浓度依赖性的相关关系[19],慢性阻塞性肺病急性加重组的白细胞计数、纤维蛋白原和D-二聚体水平显著高于稳定期慢阻肺组和健康组[20]。然而有研究指出,慢阻肺患者血清纤维蛋白原水平与疾病严重程度和动脉氧饱和度之间没有显著相关性[21]

6. D-二聚体

D-二聚体是纤维蛋白溶解后产生的一种小分子蛋白碎片,是血栓形成和溶解活动的一个重要标志。D-二聚体与慢性阻塞性肺疾病急性加重的严重程度相关,它可以用作慢性阻塞性肺疾病急性加重严重程度的评估指标,是慢性阻塞性肺疾病急性加重患者短期和长期生存的可靠预后标志物[22] [23]。在COPD急性加重期间,D-二聚体水平的升高可能表明有血栓形成和纤溶活性增强的情况,是预测严重并发症如肺栓塞的一个有用指标,它还是慢阻肺急性加重患者住院和死亡率的独立危险因素。D-二聚体水平在慢阻肺患者中增加,可被视为评估慢阻肺进展的炎症标志物,并且可以预测慢阻肺急性加重患者的预后[22] [24] [25]。D-二聚体可以提高评分工具在预测慢阻肺急性加重患者进入重症监护室概率方面的敏感性,同时具有良好的特异性[26]。在慢阻肺急性加重期,凝血系统加速激活,凝血标志物是慢阻肺急性加重和死亡率增加的潜在预测因子[27]

7. 胱抑素C

胱抑素C为具有抗氧化和抗蛋白酶活性的肽,有助于调节慢阻肺急性加重的炎症反应。Zhang等[28]研究发现,稳定期慢性阻塞性肺病患者的血清胱抑素C水平明显升高,急性加重期慢性阻塞性肺病患者的血清胱抑素C水平进一步升高。在慢性阻塞性肺病加重期和康复期,血清胱抑素C与高敏C反应蛋白呈正相关,而在慢性阻塞性肺病康复期患者中,血清胱抑素C水平与第一秒用力呼气量/用力肺活量比值呈负相关。血清胱抑素C是慢性阻塞性肺病患者的一种急性期反应物,能够预测慢性阻塞性肺病发展过程中全身炎症的发生,慢阻肺患者血清胱抑素C水平较高,吸烟能够使稳定期慢阻肺患者胱抑素C水平进一步升高。这些结果表明,胱抑素C不仅是一个肾功能的指标,也反映了慢阻肺的严重程度及其与全身炎症和代谢异常的关系[29]。总而言之,目前的荟萃分析表明,与健康人群相比,慢阻肺患者的血清胱抑素C水平更高,血清胱抑素C水平与第一秒用力呼气量/用力肺活量呈负相关,这些结果加深了对胱抑素C在慢阻肺疾病进展中作用的理解[30]。Telo等[31]研究结果显示,慢阻肺组的胱抑素C水平有所增加,胱抑素C水平升高可能与慢阻肺患者的肺功能下降和炎症有关。此外,胱抑素C水平是诊断慢阻肺的潜在指标,还有研究发现,在慢阻肺急性加重患者中,血清胱抑素C水平与住院后死亡率增加呈正相关[32]

8. 嗜酸性粒细胞

在慢性阻塞性肺病的临床诊疗中,血液中嗜酸性粒细胞水平作为预后和治疗的生物标志物显示出巨大的潜力,被认为是目前最可靠的生物标志物之一。然而,目前尚缺乏确切的血液嗜酸性粒细胞水平的特定临界值,用以指导吸入性类固醇药物和生物疗法的治疗。此外,嗜酸性粒细胞增多和其表型在慢性阻塞性肺病病程中的稳定性尚不明确,这些问题仍待解决[33]。Zeiger等[34]在研究中发现,高血液嗜酸性粒细胞计数是慢性阻塞性肺病患者未来病情加重的一个独立风险因素,因此可以以嗜酸性粒细胞为靶点进行治疗,有助于治疗相关的疾病和炎症。嗜酸性粒细胞是许多慢性阻塞性肺病患者的炎症介质[35],与嗜酸性粒细胞增多患者相比,未增多的患者入住重症监护室的比例较低。在COPD的稳定期,预测嗜酸性粒细胞加重的血细胞计数阈值为每微升300个细胞[36],高嗜酸性粒细胞计数是慢阻肺急性加重的生物标志物[37]。然而由于嗜酸性粒细胞具有变异性,因此需要在每次新的疾病加重时重新测量嗜酸性粒细胞水平[38]。嗜酸性粒细胞显著增多的患者呼吸功能受损更严重,加重更频繁[39],因此嗜酸性粒细胞可作为预防慢性阻塞性肺病急性加重以及肺功能下降的治疗靶点[40]

9. 中性粒细胞与淋巴细胞比值

中性粒细胞与淋巴细胞比值不仅可以预测慢性阻塞性肺疾病稳定期的不良预后,还可以预测慢阻肺急性加重期患者的不良预后[41]。在患有慢性阻塞性肺病的社区居民中,NLR增高与死亡风险增加相关[42]。Emami等[43]研究显示,NLR > 6.90可被视为慢阻肺急性加重患者院内死亡率增加的标志物。血液学指标,中性粒细胞与淋巴细胞比值被发现对于慢阻肺的筛查具有诊断价值,其可用于评估慢阻肺患者稳定期持续炎症和反映急性加重期疾病的严重程度[44] [45]。有临床研究发现,慢阻肺患者的NLR显著增加,在急性加重期,与稳定期相比,中性粒细胞与淋巴细胞比值显著升高。NLR与吸烟指数、慢阻肺分期和呼吸困难严重程度呈显著正相关,稳定期慢阻肺患者的NLR增加,在急性加重期进一步增加,可预测患者的死亡率[46]。稳定期NLR和血嗜酸性粒细胞增加与未来的慢阻肺急性加重相关,另有研究显示,中性粒细胞与淋巴细胞比值本身可能对预测慢阻肺急性加重价值不大,但可能包含在风险评分指数中。患有慢性阻塞性肺病的受试者,稳定期NLR或血液嗜酸性粒细胞持续升高[47],中性粒细胞与淋巴细胞比值与慢阻肺的严重程度和急性加重有关,为了预测急性加重,有研究估计基线NLR的阈值为2.7 [48]。中性粒细胞与淋巴细胞比值可用作慢性阻塞性肺疾病恶化入院的风险预测指标[49] [50]。Gomez等[51]研究发现,NLR大于5是死亡率增高的重要预测因子,可预测慢阻肺急性加重住院患者的住院时间更长。

10. 总结与展望

综上所述,血液生物标志物在慢性阻塞性肺疾病中的应用前景广阔。这些标志物不仅有助于早期诊断和病情监测,还能提供有关炎症和疾病病程的重要信息。尽管目前已有许多研究揭示了C反应蛋白、白介素-6、肿瘤坏死因子-α等标志物的病情与预后的评估价值,但仍需进一步探索其在不同患者群体中的表现差异。此外,整合多种生物标志物的信息有望提高COPD诊疗的精确度和有效性。未来研究应持续挖掘和验证新的血液生物标志物,为COPD的综合管理提供更全面的支持。

基金项目

济宁市重点研发计划(2021YXNS132)。

NOTES

*通讯作者。

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