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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">fcmedicine</journal-id><journal-title-group><journal-title xml:lang="ru">Фундаментальная и клиническая медицина</journal-title><trans-title-group xml:lang="en"><trans-title>Fundamental and Clinical Medicine</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">2500-0764</issn><issn pub-type="epub">2542-0941</issn><publisher><publisher-name>КемГМУ</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.23946/2500-0764-2022-7-1-64-69</article-id><article-id custom-type="elpub" pub-id-type="custom">fcmedicine-516</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ СТАТЬИ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>ORIGINAL RESEARCH</subject></subj-group></article-categories><title-group><article-title>Активность сигнального пути 4-1ВВ/4-1ВВL у больных тяжелой пневмонией при гриппе A/Н1N1</article-title><trans-title-group xml:lang="en"><trans-title>4-1BB/4-1BBL signaling pathway in patients with influenza A (H1N1) virus-associated pneumonia</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-0559-797X</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Малярчиков</surname><given-names>А. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Malyarchikov</surname><given-names>A. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Малярчиков Андрей Викторович, кандидат медицинских наук, заведующий кафедрой симуляционно-тренингового обучения</p><p>672000, г. Чита, ул. Горького, д. 39а</p></bio><bio xml:lang="en"><p>Andrey V. Malyarchikov, MD, PhD, Head of Simulation TrainingDepartment</p><p>39a, Gor’kogo Street, Chita, 672000</p></bio><email xlink:type="simple">malyarchikov@bk.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-3485-5176</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Шаповалов</surname><given-names>К. Г.</given-names></name><name name-style="western" xml:lang="en"><surname>Shаpovаlov</surname><given-names>K. G.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Шаповалов Константин Геннадьевич, доктор медицинских наук, профессор, заведующий кафедрой анестезиологии, реанимации и интенсивной терапии</p><p>672000, г. Чита, ул. Горького, д. 39а</p><p> </p></bio><bio xml:lang="en"><p>Konstantin G. Shapovalov, MD, DSc, Professor, Head of theDepartment of Anesthesiology, Resuscitation and Critical Care Medicine</p><p>39a, Gor’kogo Street, Chita, 672000</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>ФГБОУ ВО «Читинская государственная медицинская академия» Министерства здравоохранения Российской&#13;
Федерации</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Chita State Medical Academy</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2022</year></pub-date><pub-date pub-type="epub"><day>31</day><month>03</month><year>2022</year></pub-date><volume>7</volume><issue>1</issue><fpage>64</fpage><lpage>69</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Малярчиков А.В., Шаповалов К.Г., 2022</copyright-statement><copyright-year>2022</copyright-year><copyright-holder xml:lang="ru">Малярчиков А.В., Шаповалов К.Г.</copyright-holder><copyright-holder xml:lang="en">Malyarchikov A.V., Shаpovаlov K.G.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://fcm.kemsmu.ru/jour/article/view/516">https://fcm.kemsmu.ru/jour/article/view/516</self-uri><abstract><sec><title>Цель</title><p>Цель. Оценить активность сигнального пути 4-1ВВ/4-1ВВL у больных тяжелой пневмонией на фоне гриппа A/H1N1.</p></sec><sec><title>Материалы и методы</title><p>Материалы и методы. Обследовали 85 больных пневмонией на фоне гриппа A/H1N1. Из них 30 пациентов с тяжелой пневмонией, 55 – с нетяжелой пневмонией. Возраст пациентов составил 48 [36; 62] лет. Мужчины составляли 47,8%, а женщины – 52,2%. Критериями исключения являлись: нестабильная гемодинамика, ИМТ&gt;30, сахарный диабет, ВИЧ, туберкулез, онкопатология. Группу контроля сформировали 15 здоровых доноров. Диагноз грипп A/H1N1 подтверждался положительным результатом ПЦР-анализа. Для диагностики и оценки тяжести пневмоний использовали шкалы CURB/CRB-65; SMART-COP, а также Федеральные клинические рекомендации МЗ РФ «Внебольничная пневмония у взрослых», 2019 г. и критерии IDSA/ATS (при наличии одного «большого» или трех «малых» критериев пневмония расценивалась как «тяжелая»). Методом проточной цитофлуометрии на анализаторе Beckman Coulter (США), используя набор для мультиплексного анализа LEGENDplex™ HU Immune Checkpoint Panel 1 Beckman Coulter (США), определяли плазменную концентрацию 4-1ВВ.</p></sec><sec><title>Результаты</title><p>Результаты. Установили, что у больных тяжелой пневмонией на фоне гриппа A/H1N1 плазменная концентрация 4-1ВВ увеличивалась в 2,4 раза, у больных нетяжелой пневмонией – в 1,5 раза относительно контрольной группы, что ассоциировано с тяжестью состояния и уровнем летальности.</p></sec><sec><title>Заключение</title><p>Заключение. Сигнальный путь 4-1ВВ/4-1ВВL вовлечен в каскад реакций врожденного и адаптивного иммунитета у больных пневмониями при гриппе A/H1N1, что ассоциировано с тяжестью заболевания и уровнем летальности.</p></sec></abstract><trans-abstract xml:lang="en"><sec><title>Aim</title><p>Aim. To evaluate the activity of the 4-1BB/4-1BBL signaling pathway in patients with influenza A (H1N1) virus-associated pneumonia.</p></sec><sec><title>Materials and Methods</title><p>Materials and Methods. Here we enrolled 85 patients (41 males and 44 females, median age 48 (36-62) years) with influenza A (H1N1) virus-associated pneumonia. Among the exclusion criteria were unstable hemodynamics, BMI &gt; 30, diabetes mellitus, HIV, tuberculosis, and cancer. Control group consisted of 15 healthy donors. The diagnosis of influenza A / H1N1 was confirmed by a positive PCR test. Pneumonia was diagnosed according to the Federal Clinical Guidelines «Community-acquired pneumonia in adults». Severity of pneumonia was evaluated by using CURB-65 and SMART-COP scales as well as IDSA/ATS criteria. Plasma concentration of 4-1BB (CD137 or TNFRSF9, an inducible costimulatory receptor expressed on activated T cells and antigen-presenting cells) was determined by flow cytometry.</p></sec><sec><title>Results</title><p>Results. Patients with moderate and severe influenza A (H1N1) virus-associated pneumonia had 1.5- and 2.4 fold-increased concentration of plasma 4-1ВВ as compared with the healthy controls.</p></sec><sec><title>Conclusion</title><p>Conclusion. The 4-1BB/4-1BBL signaling pathway, involved in multiple immune reactions, is associated with the severity of influenza A (H1N1) virus-associated pneumonia.</p></sec></trans-abstract><kwd-group xml:lang="ru"><kwd>4-1ВВ</kwd><kwd>4-1ВВL</kwd><kwd>грипп A/H1N1</kwd><kwd>пневмония</kwd><kwd>системное воспаление</kwd><kwd>полиорганная недостаточность</kwd></kwd-group><kwd-group xml:lang="en"><kwd>4-1ВВ</kwd><kwd>4-1ВВL</kwd><kwd>influenza A (H1N1)</kwd><kwd>pneumonia</kwd><kwd>systemic inflammation</kwd><kwd>multiple organ failure</kwd></kwd-group><funding-group><funding-statement xml:lang="ru">Исследование выполнено при финансовом обеспечении ФГБОУ ВО «Читинская государственная медицинская академия» Министерства здравоохранения Российской Федерации.</funding-statement><funding-statement xml:lang="en">The study was financially supported by Chita State Medical Academy (Russian Federation).</funding-statement></funding-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Crimi E, Cirri S, Benincasa G, Napoli C. Epigenetics Mechanisms in Multiorgan Dysfunction Syndrome. Anesth Analg. 2019;129(5):1422-1432. https://doi.org/10.1213/ANE.0000000000004331</mixed-citation><mixed-citation xml:lang="en">Crimi E, Cirri S, Benincasa G, Napoli C. Epigenetics Mecha-nisms in Multiorgan Dysfunction Syndrome. Anesth Analg. 2019;129(5):1422-1432. https://doi.org/10.1213/ANE.0000000000004331</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Bomsztyk K, Mar D, An D, Sharifian R, Mikula M, Gharib SA, Altemeier WA, Liles WC, Denisenko O. Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction. Crit Care. 2015;19(1):225. https://doi.org/10.1186/s13054-015-0943-4</mixed-citation><mixed-citation xml:lang="en">Bomsztyk K, Mar D, An D, Sharifian R, Mikula M, Gharib SA, Altemeier WA, Liles WC, Denisenko O. Experimental acute lung injury in-duces multi-organ epigenetic modifications in key angiogenic genes impli-cated in sepsis-associated endothelial dysfunction. Crit Care. 2015;19(1):225. https://doi.org/10.1186/s13054-015-0943-4</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Черешнев В.А, Гусев Е.Ю. Иммунологические и патофизиологические механизмы системного воспаления. Медицинская иммунология. 2012;14(1-2):9-20. https://doi.org/10.15789/1563-0625-2012-1-2-9-20</mixed-citation><mixed-citation xml:lang="en">Chereshnev VA, Gusev EYu. Immunological and pathophysio-logical mechanisms of systemic inflammation. Medical Immunology (Russia). 2012;14(1-2):9-20. (In Russ). https://doi.org/10.15789/1563-0625-2012-1-2-9-20</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Рубцов М.С., Шукевич Д.Л. Современные экстракорпоральные методы лечения критических состояний, обусловленных системным воспалительным ответом (обзор литературы). Анестезиология и реаниматология. 2019;4:20-30. https://doi.org/anaesthesiology201904120</mixed-citation><mixed-citation xml:lang="en">Rubtsov MS, Shukevich DL. Modern extracorporeal methods for critical conditions caused by systemic inflammatory response (review). Russian Journal of Anaesthesiology and Reanimatology. 2019;4:20-30. (In Russ).</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Croft M, Duan W, Choi H, Eun SY, Madireddi S, Mehta A. TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. 2012;33(3):144-52. https://doi.org/10.1016/j.it.2011.10.004</mixed-citation><mixed-citation xml:lang="en">Croft M, Duan W, Choi H, Eun SY, Madireddi S, Mehta A. TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. 2012;33(3):144-52. https://doi.org/10.1016/j.it.2011.10.004</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Etxeberria I, Glez-Vaz J, Teijeira Á, Melero I. New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis. ESMO Open. 2020;4(Suppl 3):e000733. https://doi.org/10.1136/esmoopen-2020-000733</mixed-citation><mixed-citation xml:lang="en">Etxeberria I, Glez-Vaz J, Teijeira Á, Melero I. New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis. ESMO Open. 2020;4(Suppl 3):e000733. https://doi.org/10.1136/esmoopen-2020-000733</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Vinay D, Kwon B. 4-1BB signaling beyond T cells. Cell Mol Immunol. 2011;8(4): 281-284 (2011). https://doi.org/10.1038/cmi.2010.82</mixed-citation><mixed-citation xml:lang="en">Vinay D, Kwon B. 4-1BB signaling beyond T cells. Cell Mol Immunol. 2011;8(4): 281-284 (2011). https://doi.org/10.1038/cmi.2010.82</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Zapata JM, Perez-Chacon G, Carr-Baena P, Martinez-Forero I, Azpilikueta A, Otano I, Melero I. CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs. Front Immunol. 2018;9:2618. https://doi.org/10.3389/fimmu.2018.02618</mixed-citation><mixed-citation xml:lang="en">Zapata JM, Perez-Chacon G, Carr-Baena P, Martinez-Forero I, Azpilikueta A, Otano I, Melero I. CD137 (4-1BB) Signalosome: Complexi-ty Is a Matter of TRAFs. Front Immunol. 2018;9:2618. https://doi.org/10.3389/fimmu.2018.02618</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Lin GH, Sedgmen BJ, Moraes TJ, Snell LM, Topham DJ, Watts TH. Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. J Immunol. 2009;182(2):934-947. https://doi.org/10.4049/jimmunol.182.2.934</mixed-citation><mixed-citation xml:lang="en">Lin GH, Sedgmen BJ, Moraes TJ, Snell LM, Topham DJ, Watts TH. Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. J Immunol. 2009;182(2):934-947. https://doi.org/10.4049/jimmunol.182.2.934</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Bang BR, Kim SJ, Yagita H, Croft M, Kang YJ. Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice. Eur J Immunol. 2015;45(3):886-892. https://doi.org/10.1002/eji.201445174</mixed-citation><mixed-citation xml:lang="en">Bang BR, Kim SJ, Yagita H, Croft M, Kang YJ. Inhibition of 4-1BBLregulated TLR response in macrophages ameliorates endotoxininduced sepsis in mice. Eur J Immunol. 2015;45(3):886-892. https://doi.org/10.1002/eji.201445174</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Романова Е.Н, Серебрякова О.М, Говорин А.В., Филев А.П. Полиорганная дисфункция у больных гриппом H1N1/09, осложненным пневмонией. Забайкальский медицинский вестник. 2017;1:107-116. (in Russ).</mixed-citation><mixed-citation xml:lang="en">Romanova EN, Serebryakova OM, Govorin AV, Filev AP. P. Multiple organ dysfunction in patients with influenza H1N1/09 complicated by pneumonia. The Transbaikal medical bulletin. 2017;1: 107-116 (in Russ).</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Безопасность применения ремдесивира и тоцилизумаба при лечении COVID-19. Безопасность и риск фармакотерапии. 2020;8(3):160-162. https://doi.org/10.30895/2312-7821-2020-8-3-160-162</mixed-citation><mixed-citation xml:lang="en">Safety of Remdesivir and Tocilizumab in COVID-19 Treat-ment. Safety and Risk of Pharmacotherapy. 2020;8(3):160-162. (In Russ). https://doi.org/10.30895/2312-7821-2020-8-3-160-162</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, Azpilikueta A, Etxeberria I, Bolaños E, Lang V, Rodriguez M, Aznar MA, Jure-Kunkel M, Melero I. Deciphering СD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. Eur J Immunol. 2016;46(3):513-522. https://doi.org/10.1002/eji.201445388</mixed-citation><mixed-citation xml:lang="en">Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, Azpilikueta A, Etxeberria I, Bolaños E, Lang V, Rodriguez M, Aznar MA, Jure-Kunkel M, Melero I. Deciphering СD137 (4-1BB) signaling in T-cell costimulation for translation into suc-cessful cancer immunotherapy. Eur J Immunol. 2016;46(3):513-522. https://doi.org/10.1002/eji.201445388</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Yuan W, Xu C, Li B, Xia H, Pan Y, Zhong W, Xu L, Chen R, Wang B. Contributions of Costimulatory Molecule CD137 in Endothelial Cells. J Am Heart Assoc. 2021;10(11):e020721. https://doi.org/10.1161/JAHA.120.020721</mixed-citation><mixed-citation xml:lang="en">Yuan W, Xu C, Li B, Xia H, Pan Y, Zhong W, Xu L, Chen R, Wang B. Contributions of Costimulatory Molecule CD137 in Endothelial Cells. J Am Heart Assoc. 2021;10(11):e020721. https://doi.org/10.1161/JAHA.120.020721</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Jung IH, Oh GT. The roles of CD137 signaling in atherosclerosis. Korean Circ J. 2016;46:753-761. https://doi.org/10.4070/kcj.2016.46.6.753</mixed-citation><mixed-citation xml:lang="en">Jung IH, Oh GT. The roles of CD137 signaling in athero-sclerosis. Korean Circ J. 2016;46:753-761. https://doi.org/10.4070/kcj.2016.46.6.753</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Jeon HJ, Choi JH, Jung IH, Park JG, Lee MR, Lee MN, Kim B, Yoo JY, Jeong SJ, Kim DY, Park JE, Park HY, Kwack K, Choi BK, Kwon BS, Oh GT. CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation. 2010;121(9):1124-1133. https://doi.org/10.1161/CIRCULATIONAHA.109.882704</mixed-citation><mixed-citation xml:lang="en">Jeon HJ, Choi JH, Jung IH, Park JG, Lee MR, Lee MN, Kim B, Yoo JY, Jeong SJ, Kim DY, Park JE, Park HY, Kwack K, Choi BK, Kwon BS, Oh GT. CD137 (4-1BB) defi-ciency reduces atherosclerosis in hyperlipidemic mice. Circula-tion. 2010;121(9):1124-1133. https://doi.org/10.1161/CIRCULATIONAHA.109.882704</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Söderström LÅ, Tarnawski L, Olofsson PS. CD137: A checkpoint regulator involved in atherosclerosis. Atherosclerosis. 2018;272:66-72. https://doi.org/10.1016/j.atherosclerosis.2018.03.007</mixed-citation><mixed-citation xml:lang="en">Söderström LÅ, Tarnawski L, Olofsson PS. CD137: A checkpoint regulator involved in atherosclerosis. Atheroscle-rosis. 2018;272:66-72. https://doi.org/10.1016/j.atherosclerosis.2018.03.007</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Xu L, Geng T, Zang G, Bo L, Liang Y, Zhou H, Yan J. Exosome derived from CD137-modified endothelial cells regulates the Th17 responses in atherosclerosis. J Cell Mol Med. 2020;24(8):4659-4667. https://doi.org/10.1111/jcmm.15130</mixed-citation><mixed-citation xml:lang="en">Xu L, Geng T, Zang G, Bo L, Liang Y, Zhou H, Yan J. Exosome derived from CD137-modified endothelial cells regu-lates the Th17 responses in atherosclerosis. J Cell Mol Med. 2020;24(8):4659-4667. https://doi.org/10.1111/jcmm.15130</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Kwon B. Regulation of Inflammation by Bidirectional Signaling through CD137 and Its Ligand. Immune Netw. 2012;12(5):176-180. https://doi.org/10.4110/in.2012.12.5.176</mixed-citation><mixed-citation xml:lang="en">Kwon B. Regulation of Inflammation by Bidirectional Signaling through CD137 and Its Ligand. Immune Netw. 2012;12(5):176-180. https://doi.org/10.4110/in.2012.12.5.176</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
