rmtОбщая реаниматологияGeneral Reanimatology1813-97792411-7110FSBI "SRIGR" RAMS10.15360/1813-9779-2016-4-8-23rmt-1536Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL INVESTIGATIONSАЛЛЕЛЬНЫЕ ВАРИАНТЫ ГЕНОВ NRF2 И TLR9 ПРИ КРИТИЧЕСКИХ СОСТОЯНИЯХAllelic Variants of NRF2 and TLR9 Genes in Critical IllnessЧумаченкоА. Г.ChumachenkoA. G.face@neicon.ruМязинА. Е.MyazinA. E.face@neicon.ruКузовлевА. Н.KuzovlevA. N.face@neicon.ruГапоновА. М.GaponovA. M.face@neicon.ruТутельянА. В.TutelyanA. V.face@neicon.ruПороховникЛ. Н.PorokhovnikL. N.face@neicon.ruГолубевА. Н.GolubevA. M.face@neicon.ruПисаревВ. М.PisarevV. M.vpisarev@gmail.comНИИ общей реаниматологии им. В. А. Неговского,Центральный НИИ эпидемиологии РоспотребнадзораРоссияV. A. Negovsky Research Institute of General Reanimatology, Central Research Institute of Epidemiology, RospotrebnadzorRussian FederationНИИ общей реаниматологии им. В. А. Неговского, Федеральный научно-клинический центр детской гематологии, онкологии и иммунологии им. Д. Рогачева Минздрава РоссииРоссияV. A. Negovsky Research Institute of General Reanimatology, D. Rogachev Federal scientific clinical centre of pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of RussiaRussian FederationНИИ общей реаниматологии им. В. А. НеговскогоРоссияV. A. Negovsky Research Institute of General ReanimatologyRussian FederationНИИ общей реаниматологии им. В. А. Неговского, Федеральный научно#клинический центр детской гематологии, онкологии и иммунологии им. Д. Рогачева Минздрава РоссииРоссияV. A. Negovsky Research Institute of General Reanimatology, D. Rogachev Federal scientific clinical centre of pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of RussiaRussian FederationФедеральный научно#клинический центр детской гематологии, онкологии и иммунологии им. Д. Рогачева Минздрава России, Центральный НИИ эпидемиологии Роспотребнадзора, Первый Московский государственный медицинский университет им. И.М. Сеченова Минздрава РоссииРоссияD. Rogachev Federal scientific clinical centre of pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russia, Central Research Institute of Epidemiology, Rospotrebnadzor, I.M. Sechenov First Moscow State Medical University, Ministry of Healthcare of RussiaRussian FederationМедико-генетический научный центрРоссияMedical Genetics Research CenterRussian FederationНИИ общей реаниматологии им. В. А. Неговского, Федеральный научно#клинический центр детской гематологии, онкологии и иммунологии им. Д. Рогачева Минздрава России, Центральный НИИ эпидемиологии РоспотребнадзораРоссияV. A. Negovsky Research Institute of General Reanimatology, D. Rogachev Federal scientific clinical centre of pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russia, Central Research Institute of Epidemiology, RospotrebnadzorRussian Federation201626102016124823Copyright © Чумаченко А.Г., Мязин А.Е., Кузовлев А.Н., Гапонов А.М., Тутельян А.В., Пороховник Л.Н., Голубев А.Н., Писарев В.М., 20162016Чумаченко А.Г., Мязин А.Е., Кузовлев А.Н., Гапонов А.М., Тутельян А.В., Пороховник Л.Н., Голубев А.Н., Писарев В.М.Chumachenko A.G., Myazin A.E., Kuzovlev A.N., Gaponov A.M., Tutelyan A.V., Porokhovnik L.N., Golubev A.M., Pisarev V.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.reanimatology.com/rmt/article/view/1536

Цель исследования. Выявить связь аллельных вариантов сайтов однонуклеотидного полиморфизма генов NRF2 (rs6726395, 177238501A>G) и TLR9 (rs352162, 52218953T>C) — изолированно и в комплексе — с особенностями течения критических состояний при инфекции легких. Материалы и методы. Аллель#специфически генотипирована ДНК от 86 больных, перенесших хирургическое вмешательство, и онкологических больных.Результаты. Обнаружено, что у больных генотипа NRF2 177238501A>G GG с септическим шоком повышена летальность и более высокие баллы по шкале APACHE II, чаще развивался отек легких, резистентный к лечению. У больных с комбинацией генотипов NRF2 177238501A>G GG/TLR9 52218953T>C CC реже развивался септический шок и нозокомиальная пневмония.Заключение. Комбинация аллеля NRF2 177238501A>G в гомозиготном состоянии (GG) является неблагоприятной для течения и исхода критических состояний только в сочетании с аллелями TLR9 52218953T>C СT или TLR9 52218953T>C TT у больных с септическим шоком. При этом комбинация аллелей TLR9 52218953T>C СС с «неблагоприятными» NRF2 177238501A>G GG защищает от развития септи#ческого шока и нозокомиальной пневмонии.

Aim of the study. To elucidate the association of allelic variants of single nucleotide polymorphism in NRF2 (rs6726395, 177238501A>G) and TLR9 (rs352162, 52218953T>C) genes, each gene separately and in their combination, with peculiarities of the course of critical conditions during lung infection. Materials and methods. DNA from 86 post#operative patients and oncologic patients was genotyped in an allelespecific fashion using tetra#primer polymerase chain reaction followed by gel electrophoresis analysis of products.Results. It has been found that septic shock patients with NRF2 177238501A>G GG genotype had increased mortality and higher APACHE II score and developed non#responsive edema more frequently. Patients with NRF2 177238501A>G GG/TLR9 52218953T>C CC genotype combination developed septic shock and nosocomialpneumonia more rarely.Conclusion. The homozygous NRF2 177238501A>G (GG) allele combination is unfavorable for the course and outcome of critical conditions only in combination with TLR9 52218953T>C СT or TLR9 52218953T>C TT alleles in septic shock patients. At the same time, the combination of TLR9 52218953T>C СС alleles in the same patients with 'unfavorable' NRF2 177238501A>G GG protects against development of septic shock and nosocomial pneumonia.

SNPполиморфизм генов NRF2транскрипционный фактор NRF2толлподобный ре цептор TLR9септический шокнозокомиальная пневмонияSNPgene polymorphism NRF2NRF2 transcription factortolllike receptor TLR9septic shocknosocomial pneumoniaReferencesBelopolskaya O.B., Smelaya T.V., Moroz V.V., Golubev A.M., Salnikova L.E. Сlinical associations of host genetic variations in the genes of cytokines in critically ill patients. Clin. Exp. Immunol. 2015; 180 (3): 531-541. http://dx.doi.org/10.1111/cei.12592. PMID: 25619315Belopolskaya O.B., Smelaya T.V., Moroz V.V., Golubev A.M., Salnikova L.E. Сlinical associations of host genetic variations in the genes of cytokines in critically ill patients. Clin. Exp. Immunol. 2015; 180 (3): 531-541. http://dx.doi.org/10.1111/cei.12592. PMID: 25619315Мороз В.В., Смелая Т.В., Голубев А.М., Сальникова Л.Е. Генетика и медицина критических состояний: от теории к практике. Общая реаниматология. 2012; 8 (4): 5#12. http://dx.doi.org/10.15360/1813-9779-2012-4-5Moroz V.V., Smelaya T.V., Golubev A.M., Salnikova L.E. Genetika i meditsina kriticheskikh sostoyanii: ot teorii k praktike. Obshchaya Reanimatologia. [Genetics and medicine of critical conditions: from theory to practice. General Reanimatology]. 2012; 8 (4): 5-12. http://dx.doi.org/10.15360/1813-9779-2012-4-5. [In Russ.]Смелая Т.В., Сальникова Л.Е., Мороз В.В., Голубев А.М., Заржецкий Ю.В., Рубанович А.В. Генетический полиморфизм и частота развития осложнений при пневмонии различного генеза. Общая реаниматология. 2011; 7 (2): 10-16: http://dx.doi.org/10.15360/1813-9779-2011-2-10Smelaya T.V., Salnikova L.E., Moroz V.V., Golubev A.M., Zarzhetsky Yu.V., Rubanovich A.V. Genetichesky polimorfizm i chastota razvitiya oslozhnenii pri pnevmonii razlichnogo geneza. Obshchaya Reanimatologia. [Genetic polymorphism and the rate of development of complications in pneumonia of varying genesis. General Reanimatology]. 2011; 7 (2): 10-16: http://dx.doi.org/10.15360/1813-9779-2011-2-10. [In Russ.]Сальникова Л.Е., Смелая Т.В., Мороз В.В., Голубев А.М., Лаптева Н.Ш., Порошенко Г.Г., Рубанович А.В. Генетическая предрасположенность к развитию острой внебольничной пневмонии. Общая реаниматология. 2010; 6 (1): 5-10. http://dx.doi.org/10.15360/18139779-2010-1-5Salnikova L.E., Smelaya T.V., Moroz V.V., Golubev A.M., Lapteva N.Sh.,Poroshenko G.G., Rubanovich A.V. Geneticheskaya predraspolozhennost k razvitiyu ostroi vnebolnichnoi pnevmonii. Obshchaya Reanimatologia. [Genetic predisposition to the development of acute community#acquired pneumonia. General Reanimatology]. 2010; 6 (1): 5-10. http://dx.doi.org/10.15360/1813-9779-2010-1-5. [In Russ.]Сальникова Л.Е., Смелая Т.В., Мороз В.В., Голубев А.М., Понасенков Н.Х., Хоменко Р.В., Харламова И.В., Лаптева Н.Ш., Кузнецова Г.И., Порошенко Г. Г., Рубанович А.В. Гены детоксикации ксенобиотиков и их роль в развитии пневмонии. Общая реаниматология. 2008; 4 (6): 9-15. http://dx.doi.org/10.15360/1813-9779-2008-6-9Salnikova L.E., Smelaya T.V., Moroz V.V., Golubev A.M., Ponasenkov N.Kh., Khomenko R.V., Kharlamova I.V., Lapteva N.Sh., Kuznetsova G.I., Poroshenko G.G., Rubanovich A.V. Geny detoksikatsii ksenobiotikov I ikh rol v razvitii pnevmonii. Obshchaya Reanimatologia. [Xenobiotic detoxification genes and their role in the development of pneumonia. General Reanimatology]. 2008; 4 (6): 9-15. http://dx.doi.org/10.15360/1813-9779-2008-6-9. [In Russ.]Смелая Т.В., Кузовлев А.Н., Мороз В.В., Голубев А.М., БелопольскаяО.Б., Сальникова Л.Е. Молекулярно-генетические маркеры нозокомиальной пневмониии острого респираторного дистресс-синдрома. Общая реаниматология. 2015; 11 (3): 24-38. http://dx.doi.org/10.15360/1813-9779-2015-3-24-38Smelaya T.V., Kuzovlev A.N., Moroz V.V., Golubev A.M., Belopolskaya O.B., Salnikova L.E. Molekulyarno#geneticheskie markery nozokomialnoi pnevmonii ostrogo espiratornogo distress#sindroma. Obshchaya Reanimatologiya. [Search for common molecular genetic markers of nosocomial pneumonia and acute respiratory distress syndrome. General Reanimatology]. 2015; 11 (3): 24-38. http://dx.doi.org/10.15360/1813-9779-2015-3-24-38. [In Russ.]Устьянцева И.М., Хохлова О.И., Петухова О.В., Жевлакова Ю.А., Кравцова А.С., Агаджанян К.В. Некоторые аспекты формирования системного воспалительного ответа у больных в критическом состоянии. Общая реаниматология. 2010; 6 (1): 56-59. http://dx.doi.org/10.15360/1813-9779-2010-1-56Ustyantseva I.M., Khokhlova O.I., Petukhova O.V., Zhevlakova Yu.A., Kravtsova A.S., Agadzhanyan K.V. Nekotorye aspekty formirovaniya sistemnogo vospalitelnogo otveta u bolnykh v kriticheskom sostoyanii. Obshchaya Reanimatologia. [Some aspects of formation of a systemic inflammatory response in critically ill patients. General Reanimatology]. 2010; 6 (1): 56-59. http://dx.doi.org/10.15360/1813-9779-2010-1-56. [In Russ.]Shintani Y., Kapoor A., Kaneko M., Smolenski R.T., D’Acquisto F., Coppen S.R., Harada_Shoji N., Lee H.J., Thiemermann C., Takashima S., Yashiro K., Suzuki K. TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc. Natl. Acad. Sci. U S A. 2013; 110 (13): 5109-5114. http://dx.doi.org/10.1073/pnas.1219243110. PMID: 23479602Shintani Y., Kapoor A., Kaneko M., Smolenski R.T., D’Acquisto F., Coppen S.R., Harada_Shoji N., Lee H.J., Thiemermann C., Takashima S., Yashiro K., Suzuki K. TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc. Natl. Acad. Sci. U S A. 2013; 110 (13): 5109-5114. http://dx.doi.org/10.1073/pnas.1219243110. PMID: 23479602Grunwell J.R., Weiss S.L., Cvijanovich N.Z., Allen G.L., Thomas N.J., Freishtat R.J., Anas N., Meyer K., Checchia P.A., Shanley T.P., Bigham M.T., Fitzgerald J., Howard K., Frank E., Harmon K., Wong H.R. Differential expression of the Nrf2#linked genes in pediatric septic shock. Crit. Care. 2015; 19: 327. http://dx.doi.org/10.1186/s13054-015-1052-0. PMID: 26376786Grunwell J.R., Weiss S.L., Cvijanovich N.Z., Allen G.L., Thomas N.J., Freishtat R.J., Anas N., Meyer K., Checchia P.A., Shanley T.P., Bigham M.T., Fitzgerald J., Howard K., Frank E., Harmon K., Wong H.R. Differential expression of the Nrf2-linked genes in pediatric septic shock. Crit. Care. 2015; 19: 327. http://dx.doi.org/10.1186/s13054015-1052-0. PMID: 26376786Chen K.H., Zeng L., Gu W., Zhou J., Du D.Y., Jiang J.X. Polymorphisms in the toll#like receptor 9 gene associated with sepsis and multiple organ dysfunction after major blunt trauma. Br. J. Surg. 2011; 98 (9): 1252-1259. http://dx.doi.org/10.1002/bjs.7532. PMID: 21633947Chen K.H., Zeng L., Gu W., Zhou J., Du D.Y., Jiang J.X. Polymorphisms in the tollike receptor 9 gene associated with sepsis and multiple organ dysfunction after major blunt trauma. Br. J. Surg. 2011; 98 (9): 1252-1259. http://dx.doi.org/10.1002/bjs.7532. PMID: 21633947Cho H.Y., Kleeberger S.R. Noblesse oblige: NRF2 functions in the air-ways. Am. J. Respir. Cell Mol. Biol. 2014; 50 (5): 844-847. http://dx.doi.org/10.1165/rcmb.2014-0116PS. PMID: 24783956Cho H.Y., Kleeberger S.R. Noblesse oblige: NRF2 functions in the airways. Am. J. Respir. Cell Mol. Biol. 2014; 50 (5): 844-847. http://dx.doi.org/10.1165/rcmb.2014-0116PS. PMID: 24783956Khunluck T., Kukongviriyapan V., Puapairoj A., Khuntikeo N., Senggunprai L., Zeekpudsa P., Prawan A. Association of NRF2 polymorphism with cholangiocarcinoma prognosis in Thai patients. Asian Pac. J. Cancer Prev. 2014; 15 (1): 299-304. http://dx.doi.org/10.7314/APJCP.2014.15.1.299. PMID: 24528044Khunluck T., Kukongviriyapan V., Puapairoj A., Khuntikeo N., Senggunprai L., Zeekpudsa P., Prawan A. Association of NRF2 polymorphism with cholangiocarcinoma prognosis in Thai patients. Asian Pac. J. Cancer Prev. 2014; 15 (1): 299-304. http://dx.doi.org/10.7314/APJCP.2014.15.1.299. PMID: 24528044Sasaki H., Suzuki A., Shitara M., Hikosaka Y., Okuda K., Moriyama S., Yano M., Fujii Y. Polymorphisms of NRF2 gene correlated with decreased FEV1 in lung cancers of smokers. Biomed. Rep. 2013; 1 (3): 484-488. http://dx.doi.org/10.3892/br.2013.83. PMID: 24648973Sasaki H., Suzuki A., Shitara M., Hikosaka Y., Okuda K., Moriyama S., Yano M., Fujii Y. Polymorphisms of NRF2 gene correlated with decreased FEV1 in lung cancers of smokers. Biomed. Rep. 2013; 1 (3): 484-488. http://dx.doi.org/10.3892/br.2013.83. PMID: 24648973Synowiec E., Sliwinski T., Danisz K., Blasiak J., Sklodowska A., Romaniuk D., Watala C., Szaflik J., Szaflik J.P. Association between polymorphism of the NQO1, NOS3 and NFE2L2 genes and AMD. Front. Biosci. (Landmark Ed). 2013; 18: 80#90. PMID: 23276910Synowiec E., Sliwinski T., Danisz K., Blasiak J., Sklodowska A., Romaniuk D., Watala C., Szaflik J., Szaflik J.P. Association between polymorphism of the NQO1, NOS3 and NFE2L2 genes and AMD. Front. Biosci. (Landmark Ed). 2013; 18: 80#90. PMID: 23276910Marzec J.M., Christie J.D., Reddy S.P., Jedlicka A.E., Vuong H., Lanken P.N., Aplenc R., Yamamoto T., Yamamoto M., Cho H.Y., Kleeberger S.R. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 2007; 21 (9): 2237-2246. http://dx.doi.org/10.1096/fj.06-7759com. PMID: 17384144Marzec J.M., Christie J.D., Reddy S.P., Jedlicka A.E., Vuong H., Lanken P.N., Aplenc R., Yamamoto T., Yamamoto M., Cho H.Y., Kleeberger S.R. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 2007; 21 (9): 2237-2246. http://dx.doi.org/10.1096/fj.06#7759com. PMID: 17384144Yang S.I., Kim B.J., Lee S.Y., Kim H.B., Lee C.M., Yu J., Kang M.J., Yu H.S., Lee E., Jung Y.H., Kim H.Y., Seo J.H., Kwon J.W., Song D.J., Jang G., Kim W.K., Shim J.Y., Lee S.Y., Yang H.J., Suh D.I., Hong S.A., Choi K.Y., Shin Y.H., Ahn K., Kim K.W., Kim E.J., Hong S.J.; COCOA Study Group. Prenatal particulate matter/tobacco smoke increases infants’ respire-tory infections: COCOA Study. Allergy Asthma Immunol. Res. 2015; 7 (6): 573-582. http://dx.doi.org/10.4168/aair.2015.7.6.573. PMID: 26333704Yang S.I., Kim B.J., Lee S.Y., Kim H.B., Lee C.M., Yu J., Kang M.J., Yu H.S., Lee E., Jung Y.H., Kim H.Y., Seo J.H., Kwon J.W., Song D.J., Jang G., Kim W.K., Shim J.Y., Lee S.Y., Yang H.J., Suh D.I., Hong S.A., Choi K.Y., Shin Y.H., Ahn K., Kim K.W., Kim E.J., Hong S.J.; COCOA Study Group. Prenatal particulate matter/tobacco smoke increases infants’ respiratory infections: COCOA Study. Allergy Asthma Immunol. Res. 2015; 7 (6): 573-82. http://dx.doi.org/10.4168/aair.2015.7.6.573. PMID: 26333704Figarska S.M., Vonk J.M., Boezen H.M. NFE2L2 polymorphisms, mortality, and metabolism in the general population. Physiol. Genomics. 2014; 46 (12): 411#417. http://dx.doi.org/10.1152/physiolgenomics.00178.2013. PMID: 24790085Figarska S.M., Vonk J.M., Boezen H.M. NFE2L2 polymorphisms, mortality, and metabolism in the general population. Physiol. Genomics. 2014; 46 (12): 411#417. http://dx.doi.org/10.1152/physiolgenomics.00178.2013. PMID: 24790085Мороз В.В., Кузовлев А.Н., Голубев А.М., Стец В.В., Половников С.Г. Респираторная поддержка в безопасном режиме при нозокомиальной пневмонии. Общая реаниматология. 2015; 11 (2): 6-17. http://dx.doi.org/10.15360/1813-9779-2015-2-6-17Moroz V.V., Kuzovlev A.N., Golubev A.M., Stets V.V., Polovnikov S.G. Respiratornaya podderzhka v bezopasnom rezhime pri nozokomialnoi pnevmonii. Obshchaya Reanimatologia. [Safety-mode respiratory support in nosocomial pneumonia. General Reanimatology]. 2015; 11 (2): 6-17. http://dx.doi.org/10.15360/1813-977-9-2015-2-6-17. [In Russ.]Мороз В.В., Бобринская И.Г., Васильев В.Ю., Спиридонова Е.А., Тишков Е.А., Голубев А.М. Шок. Учебно#методическое пособие. М.: НИИ ОР им. В.А. Неговского РАМН; 2014: 31.Moroz V.V., Bobrinskaya I.G., Vasilyev V.Yu., Spiridonova E.A., Tishkov E.A., Golubev A.M. Shok. Uchebno#metodicheskoe posobie. [Shock. Study manual]. Moscow: NII OR imeni V.A.Negovskogo RAMN; 2014: 31. [In Russ.]Мороз В.В., Голубев А.М. Классификация острого респираторного дистрес-cиндрома. Общая реаниматология. 2007; 3 (5—6): 7—9. http://dx.doi.org/10.15360/1813-9779-2007-6-7-9Moroz V.V., Golubev A.M. Klassifikatsiya ostrogo respiratornogo distress-sindroma. Obshchaya Reanimatologia. [Classification of acute respiratory distress syndrome. General Reanimatology]. 2007; 3 (5—6): 7—9. http://dx.doi.org/10.15360/1813#9779#2007#6#7#9. [In Russ.]Мороз В.В., Голубев А.М. Принципы диагностики ранних проявлений острого повреждения легких. Общая реаниматология. 2006; 2 (4): 5—7. http://dx.doi.org/10.15360/1813-9779-2006-4-5-7Moroz V.V., Golubev A.M. Printsipy diagnostiki rannikh proyavlenii ostrogo povrezhdeniya legkikh. Obshchaya Reanimatologia. [Principles in the diagnosis of early manifestations of acute lung lesion. General Reanimatology]. 2006; 2 (4): 5—7. http://dx.doi.org/10.15360/1813-9779-2006-4-5-7. [In Russ.]Ziliene V., Kondrotas A.J., Kevelaitis E. Etiology and pathogenesis of acute respiratory failure. Medicina (Kaunas). 2004; 40 (3): 286—294. PMID: 15064552Ziliene V., Kondrotas A.J., Kevelaitis E. Etiology and pathogenesis of acute respiratory failure. Medicina (Kaunas). 2004; 40 (3): 286—294. PMID: 15064552Bernard G.R., Artigas A., Brigham K.L., Carlet J., Falke K., Hudson L., Lamy M., LeGall J.R., Morris A., Spragg R. Report of the American-European consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J. Crit. Care. 1994; 9 (1): 72—81. http://dx.doi.org/10.1016/0883#9441(94)90033-7. PMID: 8199655Bernard G.R., Artigas A., Brigham K.L., Carlet J., Falke K., Hudson L., Lamy M., LeGall J.R., Morris A., Spragg R. Report of the American-European consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J. Crit. Care. 1994; 9 (1): 72—81. http://dx.doi.org/10.1016/0883-9441(94)90033-7. PMID: 8199655Lew T.W., Kwek T.K., Tai D., Earnest A., Loo S., Singh K., Kwan K.M., Chan Y., Yim C.F., Bek S.L., Kor A.C., Yap W.S., Chelliah Y.R., Lai Y.C., Goh S.K. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA. 2003; 290 (3): 374— 380. PMID: 12865379Lew T.W., Kwek T.K., Tai D., Earnest A., Loo S., Singh K., Kwan K.M., Chan Y., Yim C.F., Bek S.L., Kor A.C., Yap W.S., Chelliah Y.R., Lai Y.C., Goh S.K. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA. 2003; 290 (3): 374— 380. PMID: 12865379Pugin J., Auckenthaler R., Mili N., Janssens J.P., Lew P.D., Suter P.M. Diagnosis of ventilator associated pneumonia by bacteriological analysis of bronchoscopic and non bronchoscopic «blind» bronchoalveolar lavage fluid. Am. Rev. Respire Dis. 1991; 143 (5 Pt 1): 1121—1129. http://dx.doi.org/10.1164/ajrccm/143.5_Pt_1.1121. PMID: 2024824Pugin J., Auckenthaler R., Mili N., Janssens J.P., Lew P.D., Suter P.M. Diagnosis of ventilator associated pneumonia by bacteriological analysis of bronchoscopic and non bronchoscopic «blind» bronchoalveolar lavage fluid. Am. Rev. Respire Dis. 1991; 143 (5 Pt 1): 1121—1129. http://dx.doi.org/10.1164/ajrccm/143.5_Pt_1.1121. PMID: 2024824Чучалин А.Г., Гельфанд Б.Р. (ред.). Нозокомиальная пневмония у взрослых. Российские национальные рекомендации. М.; 2009: 92.Chuchalin A.G., Gelfand B.R. (red.). Nozokomialnaya pnevmoniya u vzroslykh. Rossiiskie natsionalnye rekomendatsii. [Nosocomial pneumonia in adults. Russian national guidelines]. Moscow; 2009: 92. [In Russ.]Tablan O.C., Anderson L.J., Besser R., Bridges C., Hajjeh R.; CDC; Healthcare Infection Control Practices Advisory Committee. Guidelines for preventing health#care#associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm. Rep. 2004; 53 (RR#3): 1—36. PMID: 15048056Tablan O.C., Anderson L.J., Besser R., Bridges C., Hajjeh R.; CDC; Healthcare Infection Control Practices Advisory Committee. Guidelines for preventing health#care#associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm. Rep. 2004; 53 (RR#3): 1—36. PMID: 15048056Гельфанд Б.Р., Яковлев С.В., Проценко Д.Н., Белоцерковский Б.З. Нозокомиальная пневмония, связанная с искусственной вентиляцией легких: возможна ли стандартизация терапии? Consilium Medicum. 2004; 6 (4): 245—248.Gelfand B.R., Yakovlev S.V., Protsenko D.N., Belotserkovsky B.Z. Nozokomialnaya pnevmoniya, svyazannaya s iskusstvennoi ventilyatsiei legkikh: vozmozhna li standartizatsiya terapii? [Ventilator-associated nosocomial pneumonia: is there a possibility to standartoze treatment?]. Consilium Medicum. 2004; 6 (4): 245—248. [In Russ.] 29. http://www.ncbi.nlm.nih.gov/projects/SNPhttp://www.ncbi.nlm.nih.gov/projects/SNPHamajima N. PCR#CTPP: a new genotyping technique in the era of genetic epidemiology. Expert Rev. Mol. Diagn. 2001; 1 (1): 119-123. http://dx.doi.org/10.1586/14737159.1.1.119. PMID: 11901796Hamajima N. PCR#CTPP: a new genotyping technique in the era of genetic epidemiology. Expert Rev. Mol. Diagn. 2001; 1 (1): 119-123. http://dx.doi.org/10.1586/14737159.1.1.119. PMID: 11901796Salnikova L.E., Chumachenko A.G., Akaeva E.A., Kuznetsova G.I., Vesnina I.N., Lapteva N.Sh., Abilev S.K., Rubanovich A.V. Somatichesky mutagenez v limfotsitakh cheloveka v zavisimosti ot genotipov po lokusam detoksikatsii i oksidativnogo otveta. [Somatic mutagenesis in human lymphocytes depending on genotypes for detoxification and oxidative response loci]. Genetika. 2010; 46 (12): 1678#1684. PMID: 21434421. [In Russ.]Сальникова Л.Е., Чумаченко А.Г., Акаева Э.А., Кузнецова Г.И., Веснина И.Н., Лаптева Н.Ш., Абилев С.К., Рубанович А.В. Соматический мутагенез в лимфоцитах человека в зависимости от генотипов по локусам детоксикации и оксидативного ответа. Генетика. 2010; 46 (12): 1678#1684. PMID: 21434421Salnikova L.E., Chumachenko A.G., Vesnina I.N., Lapteva N.Sh., Kuznetsova G.I., Abilev S.K., Rubanovich A.V. Polimorfizm genov reparatsii i tsitogeneticheskie effekty oblucheniya. [Polymorphism of repair genes and cytogenetic radiation effects]. Radiatsionnaya Biologiya. Radioekologiya. 2010; 50 (6): 656#662. PMID: 21434392. [In Russ.]Сальникова Л.Е., Чумаченко А.Г., Веснина И.Н., Лаптева Н.Ш., Кузнецова Г.И., Абилев С.К., Рубанович А.В. Полиморфизм генов репарации и цитогенетические эффекты облучения. Радиационная биология. Радиоэкология. 2010; 50 (6): 656-662. PMID: 21434392Salnikova L.E., Chumachenko A.G., Lapteva N.S., Vesnina I.N., Kuznetsova G.I., Rubanovich A.V. Allelnye varianty polimorfnykh genov, sopryazhennye s povyshennoi chastotoi khromosomnykh aberratsii. [Allelic variants of polymorphic genes associated with a higher frequency of chromosome aberrations]. Genetika. 2011; 47 (11): 1536-1544. PMID: 22332411. [In Russ.]Сальникова Л.Е., Чумаченко А.Г., Лаптева Н.Ш., Веснина И.Н., Кузнецова Г.И., Рубанович А.В. Аллельные варианты полиморфных генов, сопряженные с повышенной частотой хромосомных аберраций. Генетика. 2011; 47 (11): 1536-1544. PMID: 22332411Makarov O.V., Kamoeva S.V., Khadzhieva M.B., Ivanova A.V., Chumachenko A.G., Abilev S.K., Salnikova L.E. Svyaz polimorfizma gena FBLN5 s riskom razvitiya prolapsatazovykh organov u zhenshchin s travmami myagkikh rodovykh putei. [Association of FBLN5 gene polymorphism with a risk for pelvic organ prolapse in women with soft tissue injuries in the generative passage]. Akusherstvo i Ginekologiya. 2015; 1: 42-50. [In Russ.]Макаров О.В., Камоева С.В., Хаджиева М.Б., Иванова А.В., Чумаченко А.Г., Абилев С.К., Сальникова Л.Е. Cвязь полиморфизма гена FBLN5 с риском развития пролапсатазовых органов у женщин с травмами мягких родовых путей. Акушерство и гинекология. 2015; 1: 42-50.Newton C.R., Graham A., Heptinstall L.E., Powell S.J., Summers C., Kalsheker N., Smith J.C., Markham A.F. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989; 17 (7): 2503#2516. http://dx.doi.org/10.1093/nar/17.7.2503. PMID: 2785681Newton C.R., Graham A., Heptinstall L.E., Powell S.J., Summers C., Kalsheker N., Smith J.C., Markham A.F. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989; 17 (7): 2503#2516. http://dx.doi.org/10.1093/nar/17.7.2503. PMID: 2785681Pujol_Lereis L.M., Schäfer N., Kuhn L.B., Rohrer B., Pauly D. Interrelation between oxidative stress and complement activation in models of age#related macular degeneration. Adv. Exp. Med. Biol. 2016; 854: 87-93. http://dx.doi.org/10.1007/978-3-319-17121-0_13. PMID: 26427398Pujol_Lereis L.M., Schäfer N., Kuhn L.B., Rohrer B., Pauly D. Interrelation between oxidative stress and complement activation in models of age#related macular degeneration. Adv. Exp. Med. Biol. 2016; 854: 87-93. http://dx.doi.org/10.1007/978-3-319-17121-0_13. PMID: 26427398Aleksunes L.M., Manautou J.E. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol. 2007; 35 (4): 459-473. http://dx.doi.org/10.1080/01926230701311344. PMID: 17562481Aleksunes L.M., Manautou J.E. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol. 2007; 35 (4): 459-473. http://dx.doi.org/10.1080/01926230701311344. PMID: 17562481Duran_Bedolla J., Montes de Oca_Sandoval M.A., Saldaña_Navor V., Villalobos_Silva J.A., Rodriguez M.C., Rivas_Arancibia S. Sepsis, mitochondrial failure and multiple organ dysfunction. Clin. Invest. Med. 2014; 37 (2): E58-E69. PMID: 24690420Duran_Bedolla J., Montes de Oca_Sandoval M.A., Saldaña_Navor V., Villalobos_Silva J.A., Rodriguez M.C., Rivas_Arancibia S. Sepsis, mitochondrial failure and multiple organ dysfunction. Clin. Invest. Med. 2014; 37 (2): E58#E69. PMID: 24690420Masuko H., Sakamoto T., Kaneko Y., Iijima H, Naito T., Noguchi E., Hirota T., Tamari M., Hizawa N. An interaction between Nrf2 polymorphisms and smoking status affects annual decline in FEV1: a longitudinal retrospective cohort study. BMC Med. Genet. 2011; 12: 97. http://dx.doi.org/10.1186/1471-2350-12-97. PMID: 21774808Masuko H., Sakamoto T., Kaneko Y., Iijima H., Naito T., Noguchi E., Hirota T., Tamari M., Hizawa N. An interaction between Nrf2 polymorphisms and smoking status affects annual decline in FEV1: a longitudinal retrospective cohort study. BMC Med. Genet. 2011; 12: 97. http://dx.doi.org/10.1186/1471#2350#12#97. PMID: 21774808Zhao G.J., Chen X., Li X.L., Yu Y.J., Hong G.L., Qiu Q.M., Li M.F., Lu Z.Q. Functional polymorphism of NRF2 gene promoter 17C/A in lipopolysaccharide-stimulated peripheral blood mononuclear cellular inflammatory response in patients with alcoholic liver disease. Zhonghua Nei Ke Za Zhi. 2013; 52 (7): 581-584. PMID: 24267001Zhao G.J., Chen X., Li X.L., Yu Y.J., Hong G.L., Qiu Q.M., Li M.F., Lu Z.Q. Functional polymorphism of NRF2 gene promoter -617C/A in lipopolysaccharide#stimulated peripheral blood mononuclear cellular inflammatory response in patients with alcoholic liver disease. Zhonghua Nei Ke Za Zhi. 2013; 52 (7): 581-584. PMID: 24267001Qiu Q.M., Zheng J.T., Nan C., Zhao Y.Y., Zhao G.J., Hong G.L., Liang H., Li M.F., Lu Z.Q. Effects of NF#E2#related factor#2 promoter polymorphism on lipopolysaccharide-induced inflammatory responses in macrophages. Zhonghua Yi Xue Za Zhi. 2013; 93 (14): 1114-1117. PMID: 23902849Qiu Q.M., Zheng J.T., Nan C., Zhao Y.Y., Zhao G.J., Hong G.L., Liang H., Li M.F., Lu Z.Q. Effects of NF#E2#related factor#2 promoter polymorphism on lipopolysaccharide#induced inflammatory responses in macrophages. Zhonghua Yi Xue Za Zhi. 2013; 93 (14): 1114-1117. PMID: 23902849Song Q., Li S., Lu Y., Hong G., Zhao G., Qiu Q., Li M., Lu Z. An association between NF#E2#related factor 2#617 C/A gene polymorphisms and sepsis in Chinese Han population. Zhonghua Nei Ke Za Zhi. 2014; 53 (6): 442-445. PMID: 25146510Song Q., Li S., Lu Y., Hong G., Zhao G., Qiu Q., Li M., Lu Z. An association between NF#E2#related factor 2#617 C/A gene polymorphisms and sepsis in Chinese Han population. Zhonghua Nei Ke Za Zhi. 2014; 53 (6): 442#445. PMID: 25146510Zuo H.P., Zhao Y.Y., Qiu Q.M., Lu Z.Q., Hong G.L., Li M.F. The effects of NF-E2-related factor-2 prompter polymorphism on alcoholic liver disease with Vibrio vulnificus sepsis. Zhonghua Yu Fang Yi Xue Za Zhi. 2011; 45 (8): 702-706. PMID: 22169690Zuo H.P., Zhao Y.Y., Qiu Q.M., Lu Z.Q., Hong G.L., Li M.F. The effects of NF-E2-related factor-2 prompter polymorphism on alcoholic liver disease with Vibrio vulnificus sepsis. Zhonghua Yu Fang Yi Xue Za Zhi. 2011; 45 (8): 702-706. PMID: 22169690Shintani Y., Drexler H.C., Kioka H., Terracciano C.M., Coppen S.R., Imamura H., Akao M., Nakai J., Wheeler A.P., Higo S., Nakayama H., Takashima S., Yashiro K., Suzuki K. Toll-like receptor 9 protects nonimmune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2. EMBO Rep. 2014; 15 (4): 438-445. http://dx.doi.org/10.1002/embr.201337945. PMID: 24610369Shintani Y., Drexler H.C., Kioka H., Terracciano C.M., Coppen S.R., Imamura H., Akao M., Nakai J., Wheeler A.P., Higo S., Nakayama H., Takashima S., Yashiro K., Suzuki K. Toll#like receptor 9 protects nonimmune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2. EMBO Rep. 2014; 15 (4): 438-445.http://www.sanger.ac.uk/science/tools/genevargene-expression-variation-archivehttp://dx.doi.org/10.1002/embr.201337945. PMID: 24610369Ishii Y., Itoh K., Morishima Y., Kimura T., Kiwamoto T., Iizuka T., Hegab A.E., Hosoya T., Nomura A., Sakamoto T., Yamamoto M., Sekizawa K. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J. Immunol. 2005; 175 (10): 6968–6975. http://dx.doi.org/10.4049/jimmunol.175.10.6968. PMID: 16272357http://www.sanger.ac.uk/science/tools/genevar-gene-expression-variation-archiveSuzuki M., Betsuyaku T., Ito Y., Nagai K., Nasuhara Y., Kaga K., Kondo S., Nishimura M. Down#regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 2008; 39 (6): 673–682. http://dx.doi.org/10.1165/rcmb.2007-0424OC. PMID: 18566336Ishii Y., Itoh K., Morishima Y., Kimura T., Kiwamoto T., Iizuka T., Hegab A.E., Hosoya T., Nomura A., Sakamoto T., Yamamoto M., Sekizawa K. Transcription factor Nrf2 plays a pivotal role in protection against elastase#induced pulmonary inflammation and emphysema. J. Immunol. 2005; 175 (10): 6968–6975. http://dx.doi.org/10.4049/jimmunol.175.10.6968. PMID: 16272357Chen H., Fang Y., Li W., Orlando R.C., Shaheen N., Chen X.L. NFkB and Nrf2in esophageal epithelial barrier function. Tissue Barriers. 2013; 1 (5): e27463. http://dx.doi.org/10.4161/tisb.27463. PMID: 24790804Suzuki M., Betsuyaku T., Ito Y., Nagai K., Nasuhara Y., Kaga K., Kondo S., Nishimura M. Down#regulated NF#E2#related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 2008; 39 (6): 673–682. http://dx.doi.org/10.1165/rcmb.2007-0424OC. PMID: 18566336Kovac S., Angelova P.R., Holmström K.M., Zhang Y., Dinkova_Kostova A.T., Abramov A.Y. Nrf2 regulates ROSproduction by mitochondria and NADPH oxidase. Biochim. Biophys. Acta. 2015; 1850 (4): 794-801. http://dx.doi.org/10.1016/j.bbagen.2014.11.021. PMID: 25484314Chen H., Fang Y., Li W., Orlando R.C., Shaheen N., Chen X.L. NFkB and Nrf2in esophageal epithelial barrier function. Tissue Barriers. 2013; 1 (5): e27463. http://dx.doi.org/10.4161/tisb.27463. PMID: 24790804Liu W., Wu H., Chen L., Wen Y., Kong X., Gao W.Q. Park7 interacts with p47(phox) to direct NADPH oxidase#dependent ROSproduction and protect against sepsis. Cell Res. 2015; 25 (6): 691-706. http://dx.doi.org/10.1038/cr.2015.63. PMID: 26021615Kovac S., Angelova P.R., Holmström K.M., Zhang Y., Dinkova_Kostova A.T., Abramov A.Y. Nrf2 regulates ROSproduction by mitochondria and NADPH oxidase. Biochim. Biophys. Acta. 2015; 1850 (4): 794-801. http://dx.doi.org/10.1016/j.bbagen.2014.11.021. PMID: 25484314Benmohamed F., Medina M., Wu Y.Z., Maschalidi S., Jouvion G., Guillemot L., Chignard M., Manoury B., Touqui L. Toll#like receptor 9 deficiency protects mice against Pseudomonas aeruginosa lung infection. PLoS One. 2014; 9 (3): e90466. http://dx.doi.org/10.1371/journal.pone.0090466. PMID: 24595157Liu W., Wu H., Chen L., Wen Y., Kong X., Gao W.Q. Park7 interacts with p47(phox) to direct NADPH oxidase#dependent ROSproduction and protect against sepsis. Cell Res. 2015; 25 (6): 691-706. http://dx.doi.org/10.1038/cr.2015.63. PMID: 26021615Osburn W.O., Kensler T.W. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat. Res. 2008; 659 (1-2): 31-39. http://dx.doi.org/10.1016/j.mrrev.2007.11.006. PMID: 18164232Benmohamed F., Medina M., Wu Y.Z., Maschalidi S., Jouvion G., Guillemot L., Chignard M., Manoury B., Touqui L. Toll#like receptor 9 deficiency protects mice against Pseudomonas aeruginosa lung infection. PLoS One. 2014; 9 (3): e90466. http://dx.doi.org/10.1371/journal.pone.0090466. PMID: 24595157Hai Dang N., Choo Y.Y., Tien Dat N., Hoai Nam N., Van Minh C., Lee J.H. 7-Methoxy-(9H-в-carbolin-1-il)-(E)-1-propenoic acid, a в-carboline alkaloid from Eurycoma longifolia, exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway. J. Cell Biochem. 2016; 117 (3): 659-670. http://dx.doi.org/10.1002/jcb.25315. PMID: 26291957Osburn W.O., Kensler T.W. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat. Res. 2008; 659 (1-2): 31-39. http://dx.doi.org/10.1016/j.mrrev.2007.11.006. PMID: 18164232Lim R., Barker G., Lappas M. The transcription factor Nrf2 is decreased after spontaneous term labour in human fetal membranes where it exerts anti-inflammatory properties. Placenta. 2015; 36 (1): 7-17. http://dx.doi.org/10.1016/j.placenta.2014.11.004. PMID: 25468547Hai Dang N., Choo Y.Y., Tien Dat N., Hoai Nam N., Van Minh C., Lee J.H. 7-Methoxy-(9H-в-carbolin-1-il)-(E)-1-propenoic acid, a в-carboline alkaloid from Eurycoma longifolia, exhibits anti#inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway. J. Cell Biochem. 2016; 117 (3): 659-670. http://dx.doi.org/10.1002/jcb.25315.PMID: 26291957Li H., Zhao J., Chen M., Tan Y., Yang X., Caudle Y., Yin D. Toll-like receptor 9 is required for chronic stress#induced immunesuppression. Neuroimmunomodulation. 2014; 21 (1): 1-7. http://dx.doi.org/10. 1159/000354610. PMID: 24080854Lim R., Barker G., Lappas M. The transcription factor Nrf2 is decreased after spontaneous term labour in human fetal membranes where it exerts antiinflammatory properties. Placenta. 2015; 36 (1): 7-17. http://dx.doi.org/10.1016/j.placenta.2014.11.004. PMID: 25468547Rose W.A. 2nd, Sakamoto K., Leifer C.A. TLR9 is important for protection against intestinal damage and for intestinal repair. Sci. Rep. 2012; 2: 574. http://dx.doi.org/10.1038/srep00574. PMID: 22893852Li H., Zhao J., Chen M., Tan Y., Yang X., Caudle Y., Yin D. Toll#ke receptor 9 is required for chronic stress#induced immunesuppression. Neuroimmunomodulation. 2014; 21 (1): 1#7. http://dx.doi.org/10.1159/000354610. PMID: 24080854Zucker S.N., Fink E.E., Bagati A., Mannava S., Bianchi_Smiraglia A., Bogner P.N., Wawrzyniak J.A., Foley C., Leonova K.I., Grimm M.J., Moparthy K., Ionov Y., Wang J., Liu S., Sexton S., Kandel E.S., Bakin A.V., Zhang Y., Kaminski N., Segal B.H., Nikiforov M.A. Nrf2 amplifies oxidative stress via induction of Klf9. Mol. Cell. 2014; 53 (6): 916#928. http://dx.doi.org/10.1016/j.molcel.2014.01.033. PMID: 24613345Rose W.A. 2nd, Sakamoto K., Leifer C.A. TLR9 is important for protection against intestinal damage and for intestinal repair. Sci. Rep. 2012; 2: 574. http://dx.doi.org/10.1038/srep00574. PMID: 22893852Rose W.A. 2nd, Sakamoto K., Leifer C.A. TLR9 is important for protection against intestinal damage and for intestinal repair. Sci. Rep. 2012; 2: 574. http://dx.doi.org/10.1038/srep00574. PMID: 22893852Zucker S.N., Fink E.E., Bagati A., Mannava S., Bianchi_Smiraglia A., Bogner P.N., Wawrzyniak J.A., Foley C., Leonova K.I., Grimm M.J., Moparthy K., Ionov Y., Wang J., Liu S., Sexton S., Kandel E.S., Bakin A.V., Zhang Y., Kaminski N., Segal B.H., Nikiforov M.A. Nrf2 amplifies oxidative stress via induction of Klf9. Mol. Cell. 2014; 53 (6): 91628. http://dx.doi.org/10.1016/j.molcel.2014.01.033. PMID: 24613345Zucker S.N., Fink E.E., Bagati A., Mannava S., Bianchi_Smiraglia A., Bogner P.N., Wawrzyniak J.A., Foley C., Leonova K.I., Grimm M.J., Moparthy K., Ionov Y., Wang J., Liu S., Sexton S., Kandel E.S., Bakin A.V., Zhang Y., Kaminski N., Segal B.H., Nikiforov M.A. Nrf2 amplifies oxidative stress via induction of Klf9. Mol. Cell. 2014; 53 (6): 91628. http://dx.doi.org/10.1016/j.molcel.2014.01.033. PMID: 24613345

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