慢性阻塞性肺疾病合并阻塞性睡眠呼吸暂停的生物标志物研究进展

doi:10.16138/j.1673-6087.2024.05.07

摘要/Abstract

摘要：

阻塞性睡眠呼吸暂停（obstructive sleep apnea，OSA）和慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）同时存在时被称为COPD-OSA重叠征，又称为重叠综合征（overlap syndrome，OS）。与单纯的OSA和COPD相比，OS患者的疾病负担更重，预后更差。由于肺功能及多导睡眠监测检查不能被广泛应用于患者，目前较多研究探讨与OS相关的免疫学、血细胞、基因蛋白、体液及其他相关的生物标志物在其辅助诊断、预测发病风险及疾病严重程度中的临床价值。本文针对目前OS相关生物学标志物的临床研究进展进行综述。

关键词: 重叠综合征, 生物标志物, 慢性阻塞性肺疾病, 阻塞性睡眠呼吸暂停

Abstract:

The coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) is referred to as COPD-OSA overlap, also known as overlap syndrome (OS). OS patients are more severe and have worse prognosis than those with OSA and COPD alone. Because pulmonary function and polysomnography cannot be conducted widely for patients, at present, there are many research to explore the clinical value of immunology, blood cell, gene protein，body fluid and other related biomarkers related to OS in assisting diagnosis, predicting the risk and severity of disease. This article reviews the recent research progress on OS-related biological markers.

Key words: Overlapping syndrome, Biomarkers, Chronic obstructive pulmonary disease, Obstructive sleep apnea

中图分类号:

R563.5

强士豪, 戴晴霞, 黄丽娜, 郭华, 崔小川. 慢性阻塞性肺疾病合并阻塞性睡眠呼吸暂停的生物标志物研究进展[J]. 内科理论与实践, 2024, 19(05): 322-327.

QIANG Shihao, DAI Qingxia, HUANG Lina, GUO Hua, CUI Xiaochuan. Research progress on biomarkers for chronic obstructive pulmonary disease complicated with obstructive sleep apnea[J]. Journal of Internal Medicine Concepts & Practice, 2024, 19(05): 322-327.

图/表 1

参考文献 45

[1]	Flenley DC. Sleep in chronic obstructive lung disease[J]. Clin Chest Med, 1985, 6(4):651-661. pmid: 2935359
[2]	Shawon MS, Perret JL, Senaratna CV, et al. Current evidence on prevalence and clinical outcomes of co-morbid obstructive sleep apnea and chronic obstructive pulmonary disease: a systematic review[J]. Sleep Med Rev, 2017, 32:58-68. doi: S1087-0792(16)00023-X pmid: 28169105
[3]	Brennan M, McDonnell MJ, Walsh SM, et al. Review of the prevalence, pathogenesis and management of OSA-COPD overlap[J]. Sleep Breath, 2022, 26(4):1551-1560. doi: 10.1007/s11325-021-02540-8 pmid: 35034250
[4]	Banjade P, Kandel K, Itani A, et al. The Interplay between obstructive sleep apnea, chronic obstructive pulmonary disease, and congestive heart failure: time to collectively refer to them as triple overlap syndrome?[J]. Medicina (Kaunas), 2023, 59(8):1374.
[5]	Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework[J]. Clin Pharmacol Ther, 2001, 69(3):89-95. doi: 10.1067/mcp.2001.113989 pmid: 11240971
[6]	Van Loo G, Bertrand MJM. Death by TNF: a road to inflammation[J]. Nat Rev Immunol, 2023, 23(5):289-303.
[7]	Chen YC, Sung HC, Chuang TY, et al. Vitamin D3 decreases TNF-α-induced inflammation in lung epithelial cells through a reduction in mitochondrial fission and mitophagy[J]. Cell Biol Toxicol, 2022, 38(3):427-450.
[8]	Higashimoto Y, Keicho N, Elliott WM, et al. Effect of adenovirus E1A on ICAM-1 promoter activity in human alveolar and bronchial epithelial cells[J]. Gene Expr, 1999, 8(5-6):287-97. pmid: 10947078
[9]	Wang Y, Hu K, Liu K, et al. Obstructive sleep apnea exacerbates airway inflammation in patients with chronic obstructive pulmonary disease[J]. Sleep Med, 2015, 16(9):1123-1130. doi: 10.1016/j.sleep.2015.04.019 pmid: 26298789
[10]	Troncoso MF, Ortiz-Quintero J, Garrido-Moreno V, et al. VCAM-1 as a predictor biomarker in cardiovascular disease[J]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(9):166170.
[11]	Wang J, Li X, Hou WJ, et al. Endothelial function and T-lymphocyte subsets in patients with overlap syndrome of chronic obstructive pulmonary disease and obstructive sleep apnea[J]. Chin Med J (Engl), 2019, 132(14):1654-1659.
[12]	Lee J, Song KH, Kim T, et al. Endothelial cell focal adhesion regulates transendothelial migration and subendothelial crawling of T cells[J]. Front Immunol, 2018, 9:48. doi: 10.3389/fimmu.2018.00048 pmid: 29472915
[13]	Liu D, Wang Z, Zhuang Y, et al. Chronic breathlessness in obstructive sleep apnea and the use of lymphocyte parameters to identify overlap syndrome among patients[J]. J Clin Med, 2023, 12(3):936.
[14]	Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease[J]. Cell Metab, 2011, 13(1):11-22. doi: 10.1016/j.cmet.2010.12.008 pmid: 21195345
[15]	Sanchez-Azofra A, Gu W, Masso-Silva JA, et al. Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome[J]. J Clin Sleep Med, 2023, 19(8):1447-1456. doi: 10.5664/jcsm.10600 pmid: 37082823
[16]	Zhou W, Li CL, Cao J, et al. Metabolic syndrome prevalence in patients with obstructive sleep apnea syndrome and chronic obstructive pulmonary disease: relationship with systemic inflammation[J]. Clin Respir J, 2020, 14(12):1159-1165.
[17]	Zeng Z, Song Y, He X, et al. Obstructive sleep apnea is associated with an increased prevalence of polycythemia in patients with chronic obstructive pulmonary disease[J]. Int J Chron Obstruct Pulmon Dis, 2022, 17:195-204.
[18]	Olivas-Martinez A, Corona-Rodarte E, Nuñez-Zuno A, et al. Causes of erythrocytosis and its impact as a risk factor for thrombosis according to etiology: experience in a referral center in Mexico City[J]. Blood Res, 2021, 56(3):166-174. doi: 10.5045/br.2021.2021111 pmid: 34462407
[19]	Rha MS, Kim CH, Yoon JH, et al. Association between the neutrophil-to-lymphocyte ratio and obstructive sleep apnea: a meta-analysis[J]. Sci Rep, 2020, 10(1):10862.
[20]	El-Gazzar AG, Kamel MH, Elbahnasy OKM, et al. Prognostic value of platelet and neutrophil to lymphocyte ratio in COPD patients[J]. Expert Rev Respir Med, 2020, 14(1):111-116.
[21]	Archontogeorgis K, Voulgaris A, Papanas N, et al. Mean platelet volume and platelet distribution width in patients with obstructive sleep apnea syndrome and concurrent chronic obstructive pulmonary disease[J]. Clin Appl Thromb Hemost, 2018, 24(8):1216-1222.
[22]	Lu C, Jiang Y, Xu W, et al. Sestrin2: multifaceted functions, molecular basis, and its implications in liver diseases[J]. Cell Death Dis, 2023, 14(2):160. doi: 10.1038/s41419-023-05669-4 pmid: 36841824
[23]	Pau MC, Zinellu A, Mangoni AA, et al. Evaluation of inflammation and oxidative stress markers in patients with obstructive sleep apnea (OSA)[J]. J Clin Med, 2023, 12(12):3935.
[24]	Miklós Z, Horváth I. The role of oxidative stress and antioxidants in cardiovascular comorbidities in COPD[J]. Antioxidants (Basel), 2023, 12(6):1196.
[25]	Heidler J, Fysikopoulos A, Wempe F, et al. Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD[J]. Dis Model Mech, 2013, 6(6):1378-1387. doi: 10.1242/dmm.013482 pmid: 24046361
[26]	Che X, Chai J, Fang Y, et al. Sestrin2 in hypoxia and hypoxia-related diseases[J]. Redox Rep, 2021, 26(1):111-116. doi: 10.1080/13510002.2021.1948774 pmid: 34225572
[27]	Chen YC, Su MC, Chin CH, et al. Formyl peptide receptor 1 up-regulation and formyl peptide receptor 2/3 down-regulation of blood immune cells along with defective lipoxin A4/resolvin D1 production in obstructive sleep apnea patients[J]. PLoS One, 2019, 22;14(5):e0216607.
[28]	George L, Mitra A, Thimraj TA, et al. Transcriptomic analysis comparing mouse strains with extreme total lung capacities identifies novel candidate genes for pulmonary function[J]. Respir Res, 2017, 18(1):152.
[29]	Xu C, Yu F, Mao S, et al. Lipoprotein-associated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome[J]. Respir Med, 2020, 163:105881.
[30]	Zhao X, Yue Y, Wang X, et al. Bioinformatics analysis of PLA2G7 as an immune-related biomarker in COPD by promoting expansion and suppressive functions of MDSCs[J]. Int Immunopharmacol, 2023, 120:110399.
[31]	Lin CC, Chen WJ, Sun YK, et al. Effects of continuous positive airway pressure on resolvin and matrix metalloproteinase-9 in patients with obstructive sleep apnea[J]. Respir Physiol Neurobiol, 2021, 285:103603.
[32]	Hao W, Li M, Zhang C, et al. Inflammatory mediators in exhaled breath condensate and peripheral blood of healthy donors and stable COPD patients[J]. Immunopharmacol Immunotoxicol, 2019, 41(2):224-230.
[33]	Wan N, Tang X, Ding H, et al. Influence of coexistence of mild OSA on airway mucus hypersecretion in patients with COPD[J]. J Breath Res, 2021, 15(2):10.
[34]	Yan W, Jiang M, Hu W, et al. Causality investigation between gut microbiota, derived metabolites, and obstructive sleep apnea: a bidirectional mendelian randomization study[J]. Nutrients, 2023, 15(21):4544.
[35]	Wei Y, Lu X, Liu C. Gut microbiota and chronic obstructive pulmonary disease: a Mendelian randomization study[J]. Front Microbiol, 2023, 14:1196751.
[36]	Palma G, Sorice GP, Genchi VA, et al. Adipose tissue inflammation and pulmonary dysfunction in obesity[J]. Int J Mol Sci, 2022, 23(13):7349.
[37]	Umar M, Sastry KS, Chouchane AI. Role of vitamin d beyond the skeletal function: a review of the molecular and clinical studies[J]. Int J Mol Sci, 2018, 19(6):1618.
[38]	Archontogeorgis K, Voulgaris A, Nena E, et al. Vitamin D levels in patients with overlap syndrome, is it associated with disease severity?[J]. J Pers Med, 2022, 12(10):1693.
[39]	Gabryelska A, Kuna P, Antczak A, et al. IL-33 mediated inflammation in chronic respiratory diseases-understanding the role of the member of IL-1 superfamily[J]. Front Immunol, 2019, 10:692. doi: 10.3389/fimmu.2019.00692 pmid: 31057533
[40]	Fiedorczuk P, Polecka A, Walasek M, et al. Potential diagnostic and monitoring biomarkers of obstructive sleep apnea-umbrella review of meta-analyses[J]. J Clin Med, 2022, 12(1):60.
[41]	黎仙, 李景云, 张媛, 等. IL-8在气道慢性炎症中的作用及研究进展[J]. 临床耳鼻咽喉头颈外科杂志, 2021, 35(12):1144-1148.
[42]	Zinellu A, Zinellu E, Pau MC, et al. A systematic review and meta-analysis of homocysteine concentrations in chronic obstructive pulmonary disease[J]. Clin Exp Med, 2023, 23(3):751-758.
[43]	Chis AF, Rajnoveanu RM, Man MA, et al. Increased vascular endothelial growth factor serum level and the role of +936C/T gene polymorphism in chronic obstructive pulmonary disease[J]. Medicina (Kaunas), 2021, 57(12):1351.
[44]	Pandey S, Garg R, Kant S, et al. Vitamin D, C-reactive protein, and oxidative stress markers in chronic obstructive pulmonary disease[J]. Tzu Chi Med J, 2019, 33(1):80-86.
[45]	He J, Li X. Relationship between chronic obstructive pulmonary disease and adiponectin concentrations: an updated meta-analysis and single-cell RNA sequencing[J]. Medicine (Baltimore), 2023, 102(33):e34825.

项目	辅助诊断	发病风险	疾病严重程度	治疗评估	预后评估
TNF-α	√		√
VCAM-1	√		√
T淋巴细胞亚群	√	√		√	√
CRP和IL-6	√
红细胞		√
NLR	√				√
MPV和PDW			√
sestrin2	√
FPR1			√
Lp-PLA2	√		√
MMP-9			√
MUC5AC	√
粪球菌属2		√
BMI		√
Vit D	√