ХРОНИЧЕСКАЯ ОБСТРУКТИВНАЯ БОЛЕЗНЬ ЛЕГКИХ: ИММУНОПАТОГЕНЕЗ И ИММУНОМОДУЛИРУЮЩАЯ ТЕРАПИЯ

Получена: 13/09/2023/ Принята: 14/09/2023 / Опубликована online: 30/10/2023
УДК 615.038
DOI 10.53511/PHARMKAZ.2023.36.74.003
А.Ю. АКПАРОВА1, Г.М. КУРМАНОВА1, Б.Т. КАМЕЛЬЖАНОВА1, А.Ж. ЖАНАЕВ1,2, Д.С. НИГМАТОВА1,2
1Казахский национальный университет им аль-Фараби,
2Городская клиническая больница №1, г. Алматы, Казахстан

ХРОНИЧЕСКАЯ ОБСТРУКТИВНАЯ БОЛЕЗНЬ ЛЕГКИХ:
ИММУНОПАТОГЕНЕЗ И ИММУНОМОДУЛИРУЮЩАЯ ТЕРАПИЯ

Резюме: Хроническая обструктивная болезнь легких (ХОБЛ) – распространенное бронхолегочное
заболевание, в развитии и прогрессировании которого важную роль играет воспалительный процесс, вызванный воздействием вредных частиц и газов. Современные научные исследования предоставляют новые сведения о воспалении и привлечении иммунных клеток при ХОБЛ. В иммунопатогенезе заболевания участвуют как врожденный, так и адаптивный компоненты иммунной
системы. Различные стимулы, такие как сигаретный дым, патоген-ассоциированные молекулярные паттерны и молекулярные паттерны, связанные с повреждением, могут активировать инфламмасому NLRP3, которая отвечает за инициацию воспалительного ответа. Воспаление характеризуется преимущественным повышением в дыхательных путях и легочной ткани альвеолярных макрофагов, нейтрофилов, лимфоцитов и врожденных лимфоидных клеток, которые вместе
со структурными клетками продуцируют цитокины, хемокины, факторы роста и липидные медиаторы. Поскольку воспаление дыхательных путей при ХОБЛ плохо поддается лечению противовоспалительными препаратами, существует потребность в создании новых методов лечения, которые могут воздействовать на молекулярные и/или клеточные мишени. Цель обзора литературы
заключалась в освещении последних достижений в изучении иммунопатогенеза и перспектив иммуномодулирующей терапии ХОБЛ.
Ключевые слова: хроническая обструктивная болезнь легких, иммунопатогенез, иммуномодуляция, инфламмасома, иммунные клетки, цитокины, хемокины
Ключевые слова: хроническая обструктивная болезнь легких, иммунопатогенез, иммуномодуляция, инфламмасома, иммунные клетки, цитокины, хемокины

СПИСОК ЛИТЕРАТУРЫ
1 Adeloye D., Song P., Zhu Y., Campbell H., Sheikh A., Rudan I. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary
disease (COPD) in 019: a systematic review and modelling analysis. Lancet Respir Med. 2022; 10: 1-12. doi: 10.1016/S2213-2600(21)00511-7.
2 Pando-Sandoval A., Ruano-Ravina A., Candal-Pedreira C., Rodríguez-García C., Represas-Represas, C. Golpe R., Fernández-Villar A., Pérez-Ríos M.
Risk factors for chronic obstructive pulmonary disease in never-smokers: A systematic review. Clinical Respiratory Journal. 2022; 16(4): 261-275. doi: 10.1111/
crj.13479.
3 Авдеев С.Н. Стратегии профилактики хронической обструктивной болезни легких. Доктор.ру. 2017; 10: 40-48.
4 Agustí A., Melén E., DeMeo D.L., Breyer-Kohansal R., Faner R. Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of
gene-environment interactions across the lifespan. Lancet Respir Med. 2022; 10(5): 512-524. doi: 10.1016/S2213-2600(21)00555-5.
5 McCartney D.L. Stevenson A.J., Hillary R.F. et al. Epigenetic signatures of starting and stopping smoking. EBioMedicine. 2018; 37: 214-220. doi: 10.1016/j.
ebiom.2018.10.051.
6 Barnes P.J. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016; 138(1):16-27. doi: 10.1016/j.
jaci.2016.05.011.
7 Rovina N., Koutsoukou A., Koulouris N.G. Inflammation and immune response in COPD: where do we stand? Mediators Inflamm. 2013; 2013:413735. doi:
10.1155/2013/413735.
8 Barnes P.J., Shapiro S.D., Pauwels R.A. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. The European Respiratory Journal.
2003; 22(4):672–688. doi: 10.1183/09031936.03.00040703.
9 David B., Bafadhel M., Koenderman L., De Soyza A. Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait. Thorax.
2021;76(2):188–195. doi:10.1136/thoraxjnl-2020-215167
10 Burgoyne R.A., Fisher A.J., Borthwick L.A. The role of epithelial damage in the pulmonary immune response. Cells. 2021; 10(10):2763. doi:10.3390/
cells10102763
11 Birrell M.A., Eltom S. The role of the NLRP3 Inflammasome in the pathogenesis of airway disease. Pharmacology and Therapeutics. 2011; 130(3):364–
370. doi: 10.1016/j.pharmthera.2011.03.007.
12 Zhang J., Xu Q., Sun W., Zhou X., Fu D., Mao L. New Insights into the Role of NLRP3 Inflammasome in Pathogenesis and Treatment of Chronic Obstructive
Pulmonary Disease. J. Inflamm. Res. 2021; 14:4155–4168. doi: 10.2147/JIR.S324323.
13 Opitz B., van Laak V., Eitel J., Suttorp N. Innate immune recognition in infectious and noninfectious diseases of the lung. The American Journal of Respiratory
and Critical Care Medicine. 2010;181(12):1294–1309. doi: 10.1164/rccm.200909-1427SO.
14 Caramori G., Casolari P., Barczyk A., Durham A.L., Di Stefano A., Adcock I. COPD immunopathology. Semin Immunopathol. 2016; 38(4):497-515. doi:
10.1007/s00281-016-0561-5.
15 Di Stefano A., Caramori G., Barczyk A., Vicari C., Brun P., Zanini A., Cappello F., Garofano E., Padovani A., Contoli M., Casolari P., Durham A.L., Chung
K.F., Barnes P.J., Papi A., Adcock I., Balbi B. Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD. Thorax. 2014;
69:516–524. doi: 10.1136/thoraxjnl-2012-203062
16 Shapiro S.D. The macrophage in chronic obstructive pulmonary disease. The American Journal of Respiratory and Critical Care Medicine. 1999; 160(5,
part 2):S29–S32. https://doi.org/10.1164/ajrccm.160.supplement_1.9
17 di Stefano A., Capelli A., Lusuardi M., et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. The American Journal
of Respiratory and Critical Care Medicine. 1998;158(4):1277–1285. doi: 10.1164/ajrccm.158.4.9802078.
18 Kotlyarov S. Involvement of the Innate Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Int J Mol Sci. 2022; 17;23(2):985.
doi: 10.3390/ijms23020985.
19 Uribe-Querol E., Rosales C. Phagocytosis: Our Current Understanding of a Universal Biological Process. Front. Immunol. 2020; 11 doi: 10.3389/
fimmu.2020.01066.
20 Hodge S., Hodge G., Ahern J., Jersmann H., Holmes M., Reynolds P.N. Smoking alters alveolar macrophage recognition and phagocytic ability: Implications
in chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 2007; 37:748–755. doi: 10.1165/rcmb.2007-0025OC.
21 Kapellos T.S., Bassler K., Aschenbrenner A.C., Fujii W., Schultze J.L. Dysregulated Functions of Lung Macrophage Populations in COPD. J. Immunol. Res.
2018; 2018:2349045. doi: 10.1155/2018/2349045.
22 Wang N., Liang H., Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front. Immunol. 2014; 5:614. doi: 10.3389/
fimmu.2014.00614.
23 Russell REK, Thorley A., Culpitt S.V., et al. Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases.
The American Journal of Physiology—Lung Cellular and Molecular Physiology. 2002; 283(4):L867–L873. https://doi.org/10.1152/ajplung.00020.2002
24 Retamales I., Elliott W.M., Meshi B., Coxson H.O., Pare P.D., Sciurba F.C., Rogers R.M., Hayashi S., Hogg J.C. Amplification of Inflammation in emphysema
and Its Association with Latent Adenoviral Infection. Am. J. Respir. Crit. Care Med. 2001;164:469–473. doi: 10.1164/ajrccm.164.3.2007149.
25 Jasper A.E., McIver W.J., Sapey E., Walton G.M. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Research.
2019;8:F1000 Faculty Rev-557. doi: 10.12688/f1000research.18411.1.
26 Barnes P.J., Shapiro S.D., Pauwels R.A. Chronic obstructive pulmonary disease: Molecular and cellularmechanisms. Eur. Respir. J. 2003;22:672–688. doi:
10.1183/09031936.03.00040703.
27 Shaykhiev R., Crystal R.G. Innate immunity and chronic obstructive pulmonary disease: A mini-review. Gerontology. 2013; 59:481–489. doi:
10.1159/000354173.
28 Freeman C.M., Curtis J.L. Lung Dendritic Cells: Shaping Immune Responses throughout Chronic Obstructive Pulmonary Disease Progression. Am. J.
Respir. Cell Mol. Biol. 2017;56:152–159. doi: 10.1165/rcmb.2016-0272TR.
29 Rogers A.V., Adelroth E., Hattotuwa K., Dewar A., Jeffery P.K. Bronchial mucosal dendritic cells in smokers and ex-smokers with COPD: An electron
microscopic study. Thorax. 2008;63:108–114. doi: 10.1136/thx.2007.078253.
30 Tsoumakidou M., Bouloukaki I., Koutala H., Kouvidi K., Mitrouska I., Zakynthinos S., Tzanakis N., Jeffery P.K., Siafakas N.M. Decreased sputum mature
dendritic cells in healthy smokers and patients with chronic obstructive pulmonary disease. Int Arch Allergy Immunol. 2009;150:389–397. https://doi.
org/10.1159/000226240
31 Zanini A., Spanevello A., Baraldo S., Majori M., Della Patrona S., Gumiero F., Aiello M., Olivieri D., Saetta M., Chetta A. Decreased maturation of dendritic
cells in the central airways of COPD patients is associated with VEGF, TGF-β and vascularity. Respiration. 2014;87:234–242.
32 Cosio M.G., Saetta M., Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. The New England Journal of Medicine. 2009;360(23):2396–
2454. DOI: 10.1056/NEJMra0804752
33 Hogg J.C., Chu F., Utokaparch S., et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. The New England Journal of
Medicine. 2004;350(26):2645–2653. DOI: 10.1056/NEJMoa032158
34 Hogg J.C., Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol. 2009;4:435–459. doi: 10.1146/annurev.
pathol.4.110807.092145.
35 Saetta M., di Stefano A., Turato G., et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. The American
Journal of Respiratory and Critical Care Medicine. 1998;157(3):822–826. DOI: 10.1164/ajrccm.157.3.9709027
36 Di Stefano A., Caramori G., Oates T., Capelli A., Lusuardi M., Gnemmi I., Ioli F., Chung K.F., Donner C.F., Barnes P.J., Adcock I.M. Increased expression
of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD. Eur Respir J. 2002;20:556–563. doi: 10.1183/09031936.02.00272002.
37 Hodge G., Holmes M., Jersmann H., et al. The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD.
Respiratory Research. 2013;14(article 63). doi: 10.1186/1465-9921-14-63

38 Halwani R., Al-Muhsen S., Hamid Q. T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 2013;143:494–501. doi: 10.1378/
chest.12-0598.
39 Miossec P., Korn T., Kuchroo V.K. Interleukin-17 and type 17 helper T cells. The New England Journal of Medicine. 2009;361(9):848–898. doi: 10.1056/
NEJMra0707449.
40 Maneechotesuwan K., Kasetsinsombat K., Wongkajornsilp A., Barnes P.J. Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17A ratio in patients
with COPD. Thorax. 2013;68:330–337. doi: 10.1136/thoraxjnl-2012-202127.
41 Olloquequi J., Ferrer J., Montes J.F., Rodríguez E., Montero M.A., García-Valero J. Differential lymphocyte infiltration in small airways and lung parenchyma
in COPD patients. Respir Med. 2010;104:1310–1318. doi: 10.1016/j.rmed.2010.03.002.
42 Brusselle G.G., Demoor T., Bracke K.R., Brandsma C.A., Timens W. Lymphoid follicles in (very) severe COPD: beneficial or harmful? Eur Respir J.
2009;34:219–230. doi: 10.1183/09031936.00150208.
43 van der Strate B.W., Postma D.S., Brandsma C.A., Melgert B.N., Luinge M.A., Geerlings M., Hylkema M.N., van den Berg A., Timens W., Kerstjens H.A.
Cigarette smoke-induced emphysema: a role for the B cell? Am J Respir Crit Care Med. 2006;173:751–758. doi: 10.1164/rccm.200504-594OC.
44 Nunez B., Sauleda J., Anto J.M., et al. Anti-tissue antibodies are related to lung function in chronic obstructive pulmonary disease. The American Journal
of Respiratory and Critical Care Medicine. 2011;183(8):1025–1031. doi: 10.1164/rccm.201001-0029OC.
45 Kirkham P.A., Caramori G., Casolari P., Papi A.A., Edwards M., Shamji B., Triantaphyllopoulos K., Hussain F., Pinart M., Khan Y., Heinemann L., Stevens L.,
Yeadon M., Barnes P.J., Chung K.F., Adcock I.M. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med. 2011;184:796–802. http://dx.doi.org/10.1164/rccm.201010-1605OC
46 Lo Bello F., Ieni A., Hansbro Ph.M., Ruggeri P., Di Stefano A., Nucera F., Coppolino I., Monaco F., Tuccari G., Adcock I. M. & Caramori G. Role of the mucins
in pathogenesis of COPD: implications for therapy, Expert Review of Respiratory Medicine. 2020;14(5):465-483, DOI: 10.1080/17476348.2020.1739525
47 Jin C., Kenny D.T., Skoog E.C., et al. Structural Diversity of Human Gastric Mucin Glycans. Mol Cell Proteomics. 2017;16(5):743-758. doi: 10.1074/mcp.
M116.067983.
48 Singanayagam A., Footitt J., Marczynski M., Radicioni G., Cross M.T., Finney L.J., Trujillo-Torralbo M.B., Calderazzo M., Zhu J., Aniscenko J., Clarke
T.B., Molyneaux P.L., Bartlett N.W., Moffatt M.F., Cookson W.O., Wedzicha J., Evans C.M., Boucher R.C., Kesimer M., Lieleg O., Mallia P., Johnston S.L.
Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease. J Clin Invest. 2022; 15;132(8):e120901. doi: 10.1172/
JCI120901.
49 Angelis N., Porpodis K., Zarogoulidis P., Spyratos D., Kioumis I., Papaiwannou A., Pitsiou G., Tsakiridis K., Mpakas A., Arikas S., Tsiouda T., Katsikogiannis
N., Kougioumtzi I., Machairiotis N., Argyriou M., Kessisis G., Zarogoulidis K. Airway inflammation in chronic obstructive pulmonary disease. J Thorac Dis. 2014;
Suppl 1:S167-72. doi: 10.3978/j.issn.2072-1439.2014.03.07.
50 Cazzola M., Hanania N.A., Page C.P., Matera M.G. Novel Anti-Inflammatory Approaches to COPD. Int J Chron Obstruct Pulmon Dis. 2023;18:1333-1352
https://doi.org/10.2147/COPD.S419056
51 Matera M.G., Cazzola M., Page C. Prospects for COPD treatment. Curr Opin Pharmacol. 2021;56:74–84. doi:10.1016/j.coph.2020.11.003
52 Singh R., Mackay A. J., Patel A. R., et al Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive
pulmonary disease[J]. Respiratory Research. 2014; 15(1):1—10. doi: 10.1186/s12931-014-0114-1.
53 Kobayashi Y., Wada H., Rossios C., Takagi D., Charron C., Barnes P.J., et alA novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid
insensitivity via phosphoinositide 3-kinase pathway inhibition. Br J Pharmacol. 2013; 169(5):1024–34. https://doi.org/10.1111/bph.12187[PubMed]0007-1188
54 van Eeden S. F.; Hogg J. C. Immune-Modulation in Chronic Obstructive Pulmonary Disease: Current Concepts and Future Strategies. Respiration. 2020;
99 (7): 550–565. https://doi.org/10.1159/000502261
55 Candela M., Costorella R., Stassaldi A. et al. Treatment of COPD: the simplicity is a resolved complexity. Multidiscip Respir Med. 2019; 14(18). https://doi.
org/10.1186/s40248-019-0181-8
56 Matera M.G., Page C.P., Cazzola M. Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol Sci.
2011; 32(8):495–506. https://doi.org/10.1016/j.tips.2011.04.003
57 Rennard S.I., Calverley P.M.A., Goehring U.M., Bredenbröker D., Martinez F.J. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance
of defining different subsets of patients with COPD. Respir Res. 2011;12:18. doi: 10.1186/1465-9921-12-18.
58 Balazs Antus. Pharmacotherapy of Chronic Obstructive Pulmonary Disease: A Clinical Review. International Scholarly Research Notices. 2013. Article ID
582807 | https://doi.org/10.1155/2013/582807
59 Eltboli O., Mistry V., Barker B., Brightling C.E. Relationship between blood and bronchial submucosal eosinophilia and reticular basement membrane
thickening in chronic obstructive pulmonary disease. Respirology. 2015;20(4):667–670. doi:10.1111/resp.12475
60 Brightling C.E., Bleecker E.R., Panettieri R.A. Jr, Bafadhel M, She D., Ward C.K., et al Benralizumab for chronic obstructive pulmonary disease and
sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891–901. https://doi.org/10.1016/S2213-
2600(14)70187-0
61 Lange P., Ahmed E., Lahmar Z.M., Martinez F.J., Bourdin A. Natural history, and mechanisms of COPD. Respirology. 2021;26(4):298–321. doi:10.1111/
resp.14007
62 Matera M.G., Calzetta L., Cazzola M., Ora J., Rogliani P. Biologic therapies for chronic obstructive pulmonary disease. Expert Opin Biol Ther. 2023;23(2):163–
173. doi:10.1080/14712598.2022.2160238
63 Bhatt S.P., Rabe K.F., Hanania N.A., et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023. doi:10.1056/
NEJMoa2303951
64 Sun J., Liu T., Yan Y., et al. The role of Th1/Th2 cytokines played in regulation of specific CD4+ Th1 cell conversion and activation during inflammatory
reaction of chronic obstructive pulmonary disease. Scand J Immunol. 2018;88(1):e12674. doi:10.1111/sji.12674
65 Bautista M.V., Chen Y., Ivanova V.S., Rahimi M.K., Watson A.M., Rose M.C. IL-8 regulates mucin gene expression at the posttranscriptional level in lung
epithelial cells. J Immunol. 2009; 183(3):2159–66. https://doi.org/10.4049/jimmunol.0803022
66 Thatcher T.H., McHugh N.A., Egan R.W., et al. Role of CXCR2 in cigarette smoke-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol.
2005;289(2):L322–L328. doi:10.1152/ajplung.00039.2005
67 Lazaar A.L., Miller B.E., Donald A.C., et al. CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion:
a phase 2b trial. Respir Res. 2020;21(1):149. doi:10.1186/s12931-020-01401-4
68 Wells A.D., Woods A., Hilleman D.E., Malesker M.A. Alpha-1 Antitrypsin Replacement in Patients With COPD. 2019;44(7):412-415. PMID: 31258312
69 Kalfopoulos M., Wetmore K., ElMallah M.K. Pathophysiology of alpha-1 antitrypsin lung disease. Methods Mol Biol. 2017;1639:9–19. doi: 10.1007/978-1-
4939-7163-3_2.
70 Gøtzsche P.C., Johansen H.K. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung
disease. Cochrane Database Syst Rev. 2016;9(9):CD007851. https://doi.org/10.1002/14651858.CD007851.pub3[PubMed]1469-493X
71 Stolk J., Tov N., Chapman K.R., et al. Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations
of COPD. Eur Respir J. 2019;54(5):1900673. doi:10.1183/13993003.00673-2019

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