mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-SOA-2930mimmun-2930Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESЗначение оценки воспалительных маркеров активации сосудистой стенки при возрастной макулярной дегенерацииSignificance of assessing the inflammatory markers of vascular wall activation in age-related macular degenerationhttps://orcid.org/0000-0001-8007-6643БалацкаяН. В.BalatskayaN. V.

Балацкая Наталья Владимировна – к.б.н., ведущий научный сотрудник, начальник отдела иммунологии и вирусологии 

Москва

Balatskaya Natalia V., PhD (Biology), Leading Researcher, Head, Department of Immunology and Virology

Moscow

balnat07@rambler.ruhttps://orcid.org/0009-0005-9638-1147ВоробьеваЕ. П.VorobyovaE. P.

Воробьева Елена Павловна – младший научный сотрудник отдела иммунологии и вирусологии 

Москва

Vorobyova Elena P., Junior Researcher, Department of Immunology and Virology

Moscow

helen1996@list.ruhttps://orcid.org/0000-0002-1005-5633КуликоваИ. Г.KulikovaI. G.

Куликова Ирина Геннадьевна – биолог вирусологической микробиологической лаборатории отдела иммунологии и вирусологии 

Москва

Kulikova Irina G., Biologist, Virology-Microbiology Laboratory, Department of Immunology and Virology

Moscow

ig-kulikova@yandex.ruhttps://orcid.org/0009-0008-2823-5297АндрюшинА. Е.AndryushinA. E.

Андрюшин Александр Евгеньевич – научный сотрудник отдела иммунологии и вирусологии 

Москва

 

Andryushin Alexander E., Researcher, Department of Immunology and Virology

Moscow

gradmalexander@gmail.comФГБУ «Национальный медицинский исследовательский центр глазных болезней имени Гельмгольца» Министерства здравоохранения РФРоссияHelmholtz National Medical Research Center of Eye DiseasesRussian Federation202507072025274863872Copyright © Балацкая Н.В., Воробьева Е.П., Куликова И.Г., Андрюшин А.Е., 20252025Балацкая Н.В., Воробьева Е.П., Куликова И.Г., Андрюшин А.Е.Balatskaya N.V., Vorobyova E.P., Kulikova I.G., Andryushin A.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2930

Среди многочисленных факторов патогенеза возрастной макулярной дегенерации (ВМД) в последние годы особое внимание уделяют эндотелиальной дисфункции (ЭД), поскольку эндотелий сосудов является важнейшим элементом внутренней области гематоретинального барьера (ВГРБ), обеспечивающему иммунологический гомеостаз сетчатки. Изучение воспалительных маркеров активации эндотелия представляется актуальным с целью понимания механизмов развития заболевания, может способствовать разработке патогенетической терапии ранней и промежуточной стадий ВМД, мер вторичной профилактики ее осложнений. Цель – определение sICAM-1, sVCAM-1, sE-selectin, sP-selectin и МСР-1/CCL2 в сыворотке крови (СК) и слезной жидкости (СЖ) пациентов с начальной (AREDS2) и промежуточной (AREDS3) стадиями ВМД. Исследование проведено методом проточной цитометрии (CBA) (проточный цитометр BD FACS Canto II, США) с помощью панели, сконструированной из совместимых симплексных тест-систем FlowCytomixTM (Bender MedSystem GmbH, Германия) для определения sICAM-1, sVCAM-1, sE-selectin, sP-selectin и МСР-1/CCL2, позволяющей осуществлять их одновременную детекцию, с обработкой данных в пакете FlowCytomix Pro v. 6.0 (BenderMed Systems GmbH, Германия). Выявлена тенденция к повышению уровня sVCAM-1 в СК пациентов группы с промежуточной ВМД по сравнению с нормой. При анализе системной продукции остальных маркеров не установлено различий между основными группами и возрастным контролем. В ходе исследования СЖ в группе AREDS2 обнаружено достоверное увеличение концентрации МСР-1/CCL2, sE-selectin (р < 0,05) с тенденцией к усилению локальной продукции растворимых ICAM-1 и P-selectin (р = 0,05) относительно нормы. В группе AREDS3 значимые сдвиги касались 3 факторов sICAM-1, sE-selectin и sP-selectin, содержание которых в СЖ пациентов превышало таковое в контроле более чем в 2,5, почти в 5 и 2 раза соответственно (р < 0,05). Выявлено преимущественно усиление локальной и в меньшей мере системной продукции маркеров, отражающее активированное состояние эндотелия. Полученные данные представляются важными, поскольку доказывают участие sICAM-1, sVCAM-1, sE-selectin, sP-selectin, МСР-1/CCL2 в патогенезе заболевания и позволяют думать о компроментации гематоретинального барьера, необходимости дополнения курса терапии ВМД назначением препаратов ангиопротекторного, противовоспалительного действия и нуждается в дальнейшем изучении.

Among the numerous pathogenetic factors of age-related macular degeneration (AMD), special attention has been recently paid to endothelial dysfunction (ED), since the vascular endothelium is an important internal component of the the hematoretinal barrier (IBRB) providing immunological homeostasis of the retina. The study of inflammatory endothelial activation markers seems relevant in terms of understanding the mechanisms of disease development, potentially contributing to the development of pathogenetic therapy at early and intermediate stages of AMD as well as secondary prevention of its complications. The aim of the present: study was to determine sICAM-1, sVCAM-1, sE-selectin, sP-selectin and MCP-1/CCL2 in blood serum (BS) and tear fluid (TF) of patients with initial (AREDS2) and intermediate (AREDS3) stages of AMD. The study was performed by flow cytometry (CBA) with BD FACS Canto II flow cytometer, USA), using a diagnostic panel based on compatible simplex Flow CytomixTM test systems (Bender Med System GmbH, Germany) to determine sICAM-1, sVCAM-1, sE-selectin, sP-selectin and MCP-1/CCL2 thus allowing their simultaneous detection followed by data processing in the FlowCytomix Pro v. 6.0 package (BenderMed Systems GmbH, Germany). We have revealed a tendency to increased serum sVCAM-1 in the AREDS3 group compared to the reference values. When studying tear fluid in the AREDS2 group, a significant increase in MCP-1, sE-selectin concentrations was found (p < 0.05), along with a tendency to increased local production of sICAM-1 and sP-selectin (p = 0.05) against normal levels. Significant shifts in the AREDS3 group concerned three 3 factors in tear fluid, i.e., sICAM-1, sE-selectin and sP-selectin, that exceeded control levels by 2.5, 5 and 2 times, respectively (p < 0.05). The obtained data are important because they presume a role of sICAM-1, sVCAM-1, sE-selectin, sP-selectin, MCP-1/CCL2 in pathogenesis of the disorder and allows us to suggest a compromised state of blood retinal barrier, thus requiring supplementation of AMD therapy with angioprotectives, antiinflammatory drugs, and needs further studies.

возрастная макулярная дегенерациядисфункция эндотелия сосудоввоспалениемаркерымолекулы адгезиихемокиныage-related macular degenerationvascular endothelialdysfunctioninflammationmarkersadhesion moleculeschemokinesReferencesВасина Л.В., Петрищев Н.Н., Власов Т.Д. Эндотелиальная дисфункция и ее основные маркеры // Регионарное кровообращение и микроциркуляция, 2017. Т. 16, № 1. С. 4-15.Vasina L.V., Petrishchev N.N., Vlasov T.D. Endothelial dysfunction and its main markers. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation, 2017, Vol. 16, no. 1, pp. 4-15. (In Russ.)Нероев В.В., Балацкая Н.В., Нероева Н.В., Кармокова А.Г., Рябина М.В., Куликова И.Г. Скрининг цитокинов в сыворотке крови и слезной жидкости при влажной и атрофической формах возрастной макулярной дегенерации // Медицинская иммунология, 2022. Т. 24, № 1. С. 157-170. doi: 10.15789/1563-0625-SOC-2351.Neroev V.V., Balatskaya N.V., Neroeva N.V., Karmokova A.G., Ryabina M.V., Kulikova I.G. Screening of cytokines in blood serum and tear fluid in wet and atrophic forms of age-related macular degeneration. Meditsinskaya immunologiya = Medical Immunology (Russia), 2022, Vol. 24, no. 1, pp. 157-170. (In Russ.) doi: 10.15789/1563-0625-SOC-2351.Пестрякова Я.Ф., Рыбченко А.А., Шабанов Г.А., Запорожец Т.С. Закономерности изменений биоэлектрической активности головного мозга при возрастной макулярной дегенерации // Тихоокеанский медицинский журнал, 2017. № 2. С. 26-29. doi: 10.17238/PmJ1609-1175.2017.2.26-29.Pestryakova Ya.F., Rybchenko A.A., Shabanov G.A., Zaporozhets T.S. Patterns of changes in bioelectrical activity of the brain during age-related macular degeneration. Tikhookeanskiy meditsinskiy zhurnal = Pacific Medical Journal, 2017, no. 2, pp. 26-29. (In Russ.) doi: 10.17238/PmJ1609-1175.2017.2.26-29.Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of highdose supplementation with vitamins C and E, betacarotene, and zinc for age-related macular degeneration and vision loss: AREDS. Arch. Ophthalmol., 2001, Vol. 119, pp. 1417-1436.Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of highdose supplementation with vitamins C and E, betacarotene, and zinc for age-related macular degeneration and vision loss: AREDS. Arch. Ophthalmol., 2001, Vol. 119, pp. 1417-1436.Bhutto I.A., Baba T., Merges C., McLeod D.S., Lutty G.A. Low nitric oxide synthases (NOSs) in eyes with age-related macular degeneration (AMD). Exp. Eye Res., 2010, Vol. 90, no. 1, pp. 155-167.Bhutto I.A., Baba T., Merges C., McLeod D.S., Lutty G.A. Low nitric oxide synthases (NOSs) in eyes with age-related macular degeneration (AMD). Exp. Eye Res., 2010, Vol. 90, no. 1, pp. 155-167.Binder F.P.C., Ernst B. E- and P-selectin: differences, similarities and implications for the design of P-selectin antagonists. Chimia (Aarau), 2011, Vol. 65, no. 4, pp. 210-213.Binder F.P.C., Ernst B. E- and P-selectin: differences, similarities and implications for the design of P-selectin antagonists. Chimia (Aarau), 2011, Vol. 65, no. 4, pp. 210-213.Buschini E., Piras A., Nuzzi R., Vercelli A. Age related macular degeneration and drusen: neuroinflammation in the retina. Prog. Neurogibol., 2011, Vol. 95, no. 1, pp. 14-25.Buschini E., Piras A., Nuzzi R., Vercelli A. Age related macular degeneration and drusen: neuroinflammation in the retina. Prog. Neurogibol., 2011, Vol. 95, no. 1, pp. 14-25.Chaitanya G.V., Cromer W., Wells S., Jennings M., Mathis J.M., Minagar A., Alexander J.S. Metabolic modulation of cytokine-induced brain endothelial adhesion molecule expression. Microcirculation, 2012, Vol. 19, no. 2, pp. 155-165.Chaitanya G.V., Cromer W., Wells S., Jennings M., Mathis J.M., Minagar A., Alexander J.S. Metabolic modulation of cytokine-induced brain endothelial adhesion molecule expression. Microcirculation, 2012, Vol. 19, no. 2, pp. 155-165.Chakravarthy U., Wong T.Y., Fletcher A., Piault E., Evans C., Zlateva G., Buggage R., Pleil A., Mitchell P. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol., 2010, Vol. 10, 31. doi: 10.1186/1471-2415-10-31.Chakravarthy U., Wong T.Y., Fletcher A., Piault E., Evans C., Zlateva G., Buggage R., Pleil A., Mitchell P. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol., 2010, Vol. 10, 31. doi: 10.1186/1471-2415-10-31.Clemons T.E., Milton R.C., Klein R., Seddon J.M., Ferris F.L. Risk factors for the incidence of Advanced Age–Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology, 2005, Vol. 112, no. 4, pp. 533-539.Clemons T.E., Milton R.C., Klein R., Seddon J.M., Ferris F.L. Risk factors for the incidence of Advanced Age–Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology, 2005, Vol. 112, no. 4, pp. 533-539.Combadiere C., Potteaux S., Rodero M., Simon T., Pezard A., Esposito B., Merval R., Proudfoot A., Tedgui A., Mallat Z. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation, 2008, Vol. 117, no. 13, pp. 1649-1657.Combadiere C., Potteaux S., Rodero M., Simon T., Pezard A., Esposito B., Merval R., Proudfoot A., Tedgui A., Mallat Z. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation, 2008, Vol. 117, no. 13, pp. 1649-1657.Du Z., Wu X., Song M., Li P., Wang L. Oxidative damage induces MCP-1 secretion and macrophage aggregation in age-related macular degeneration (AMD). Graefes Arch. Clin. Exp. Ophthalmol., 2016, Vol. 254, no. 12, pp. 2469-2476.Du Z., Wu X., Song M., Li P., Wang L. Oxidative damage induces MCP-1 secretion and macrophage aggregation in age-related macular degeneration (AMD). Graefes Arch. Clin. Exp. Ophthalmol., 2016, Vol. 254, no. 12, pp. 2469-2476.Dunbar H.M.P., Behning С., Abdirahman А., Higgins В.Е., Binns А.М., Terheyden J.H., Zakaria N., Poor S., Finger R.P., Leal S., Holz F.G., Schmid M., Crabb D.P., Rubin G.S., Luhmann U.F.O. Repeatability and discriminatory power of chart-based visual function tests in individuals with age-related macular degeneration: A MACUSTAR Study Report. JAMA Ophthalmol., 2022, Vol. 140, no. 8, pp. 780-789.Dunbar H.M.P., Behning С., Abdirahman А., Higgins В.Е., Binns А.М., Terheyden J.H., Zakaria N., Poor S., Finger R.P., Leal S., Holz F.G., Schmid M., Crabb D.P., Rubin G.S., Luhmann U.F.O. Repeatability and discriminatory power of chart-based visual function tests in individuals with age-related macular degeneration: A MACUSTAR Study Report. JAMA Ophthalmol., 2022, Vol. 140, no. 8, pp. 780-789.Edlinger C., Lichtenauer M., Wernly B., Pistulli R., Paar V., Prodinger C., Krizanic F., Thieme M., Kammler J., Jung C., Hoppe U.C., Schulze P.C., Kretzschmar D. Disease-specific characteristics of vascular cell adhesion molecule-1 levels in patients with peripheral artery disease. Heart Vessels, 2019, Vol. 34, no. 6, pp. 976-983.Edlinger C., Lichtenauer M., Wernly B., Pistulli R., Paar V., Prodinger C., Krizanic F., Thieme M., Kammler J., Jung C., Hoppe U.C., Schulze P.C., Kretzschmar D. Disease-specific characteristics of vascular cell adhesion molecule-1 levels in patients with peripheral artery disease. Heart Vessels, 2019, Vol. 34, no. 6, pp. 976-983.Horani М., Mahmood S., Aslam T.M. A review of macular atrophy of the retinal pigment epithelium in patients with neovascular age-related macular degeneration: What is the link? Part II. Ophthalmol. Ther., 2020, Vol. 9, no. 1, pp. 35-75.Horani М., Mahmood S., Aslam T.M. A review of macular atrophy of the retinal pigment epithelium in patients with neovascular age-related macular degeneration: What is the link? Part II. Ophthalmol. Ther., 2020, Vol. 9, no. 1, pp. 35-75.Hossain M., Qadri S.M., Liu L. Inhibition of nitric оxide synthesis enhances leukocyte rolling and adhesion in human microvasculature. J. Inflamm. (Lond.), 2012, Vol. 9, 28. doi: 10.1186/1476-9255-9-28.Hossain M., Qadri S.M., Liu L. Inhibition of nitric оxide synthesis enhances leukocyte rolling and adhesion in human microvasculature. J. Inflamm. (Lond.), 2012, Vol. 9, 28. doi: 10.1186/1476-9255-9-28.Huang R.B., Gonzalez A.L., Eniola-Adefeso O. Laminar shear stress elicit distinct endothelial cell E-selectin expression pattern via TNFα and IL-1β activation. Biotechnol. Bioeng., 2013, Vol. 110, no. 3, pp. 999-1003.Huang R.B., Gonzalez A.L., Eniola-Adefeso O. Laminar shear stress elicit distinct endothelial cell E-selectin expression pattern via TNFα and IL-1β activation. Biotechnol. Bioeng., 2013, Vol. 110, no. 3, pp. 999-1003.Hudson N., Celkova L., Hopkins A., Greene C., Storti F., Ozaki E., Fahey E., Theodoropoulou S., Kenna P.F., Humphries M.M., Curtis A.M., Demmons E., Browne A., Liddie S., Lawrence M.S., Grimm C., Cahill M.T., Humphries P., Doyle S.L., Campbell M. Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy. JCI Insight, 2019, Vol. 4, no. 15, e130273. doi: 10.1172/jci.insight.130273.Hudson N., Celkova L., Hopkins A., Greene C., Storti F., Ozaki E., Fahey E., Theodoropoulou S., Kenna P.F., Humphries M.M., Curtis A.M., Demmons E., Browne A., Liddie S., Lawrence M.S., Grimm C., Cahill M.T., Humphries P., Doyle S.L., Campbell M. Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy. JCI Insight, 2019, Vol. 4, no. 15, e130273. doi: 10.1172/jci.insight.130273.Nian S., Lo A.C.Y., Mi Y., Ren K., Yang D. Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets. Eye Vis. (Lond.), 2021, Vol. 8, 15. doi: 10.1186/s40662-021-00239-1.Nian S., Lo A.C.Y., Mi Y., Ren K., Yang D. Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets. Eye Vis. (Lond.), 2021, Vol. 8, 15. doi: 10.1186/s40662-021-00239-1.Schultz H., Song Y., Baumann B.H., Kapphahn R.J., Montezuma S.R., Ferrington D.A., Dunaief J.L. Increased serum proteins in non-exudative AMD retinas. Exp. Eye Res., 2019, 186, 107686. doi: 10.1016/j.exer.2019.05.026.Schultz H., Song Y., Baumann B.H., Kapphahn R.J., Montezuma S.R., Ferrington D.A., Dunaief J.L. Increased serum proteins in non-exudative AMD retinas. Exp. Eye Res., 2019, 186, 107686. doi: 10.1016/j.exer.2019.05.026.Tzoulaki I., Murray G.D., Lee A.J., Rumley A., Lowe G.D.O., Gerald F., Fowkes R. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation, 2005, Vol. 112, no. 7, pp. 976-983.Tzoulaki I., Murray G.D., Lee A.J., Rumley A., Lowe G.D.O., Gerald F., Fowkes R. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation, 2005, Vol. 112, no. 7, pp. 976-983.Vasan R.S. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation, 2006, Vol. 113, pp. 2335-2362.Vasan R.S. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation, 2006, Vol. 113, pp. 2335-2362.Wong W.L., Su X., Li X., Cheung C.M., Klein R., Cheng C.Y., Wong T.Y. Global prevalence of age-related macular degeneration and disease burdenprojection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health, 2014, Vol. 2, no. 2, pp. e106-e116.Wong W.L., Su X., Li X., Cheung C.M., Klein R., Cheng C.Y., Wong T.Y. Global prevalence of age-related macular degeneration and disease burdenprojection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health, 2014, Vol. 2, no. 2, pp. e106-e116.Zhang J. Biomarkers of endothelial activation and dysfunction in cardiovascular diseases. Rev. Cardiovasc. Med., 2022, Vol. 23, no. 2, 73. doi: 10.31083/j.rcm2302073.Zhang J. Biomarkers of endothelial activation and dysfunction in cardiovascular diseases. Rev. Cardiovasc. Med., 2022, Vol. 23, no. 2, 73. doi: 10.31083/j.rcm2302073.

The authors declare that there are no conflicts of interest present.