vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2020-17-3-364-371vestim-696Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEЭкспрессия рецепторов мелатонина при гастроэзофагеальной рефлюксной болезни, ассоциированной с синдромом обструктивного апноэ/гипопноэ во снеExpression of melatonin receptors in the gastroesophageal reflux disease associated with obstructive sleep apnea/hypopnea syndromeКарповичО. А.KarpovichA. A.

Карпович Олеся Анатольевна – ассистент

ул. Горького, 80, 230009, г. Гродно

Alesia А. Karpovich – Аssistant

80, Gorky Str., 230009, Grodno

olesjakarpovich@rambler.ruШишкоВ. И.ShyshkoV. I.

Шишко Виталий Иосифович – кандидат медицинских наук, доцент, проректор

ул. Горького, 80, 230009, г. Гродно

Vitaliy I. Shyshko – Ph. D. (Med.), Associate Professor, Vice-rector

80, Gorky Str., 230009, Grodno

vshyshko@mail.ruГродненский государственный медицинский университетGrodno State Medical University202029082020173364371Copyright © Карпович О.А., Шишко В.И., 20202020Карпович О.А., Шишко В.И.Karpovich A.A., Shyshko V.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/696

Оценена экспрессия рецепторов мелатонина (MTNR1B) в слизистой оболочке пищевода при гастроэзофагеальной рефлюксной болезни (ГЭРБ), ассоциированной с синдромом обструктивного апноэ/гипопноэ во сне (СОАГС), и изучена связь выявленных изменений с тяжестью апноэ сна. Обследовано 25 пациентов с ГЭРБ (группа 1), 23 – с ГЭРБ в сочетании с СОАГС (группа 2) и 18 – с СОАГС (группа 3). Средний возраст обследуемых – 48,1 ±  9,8 года. Группа сравнения (группа 4) включала 18 человек без ГЭРБ и апноэ во сне. Экспрессию MTNR1B в слизистой оболочке пищевода определяли иммуногистохимическим методом, используя специфические антитела. Статистический анализ материала проводили с помощью пакета программ Statistica 10.0. Показано, что у пациентов группы 2 более высокая интенсивность экспрессии MTNR1B, чем у пациентов группы 1 (0,122 [0,064; 0,266] vs 0,620 [0,332; 0,983]; р  =  0,00001) и группы 3 (0,620 [0,332; 0,983] vs 0,232 [0,120; 0,418]; р = 0,0098). Отмечалось увеличение интенсивности экспрессии MTNR1B с нарастанием тяжести апноэ во сне: 0,295 [0,198; 0,403] у пациентов с апноэ легкой степени тяжести против 0,941 [0,345; 0,992] у пациентов с апноэ средней и тяжелой степени (р = 0,0021). Выявлена прямая связь интенсивности экспрессии MTNR1B со степенью тяжести апноэ во сне (r = 0,50; р = 0,0016). Установлено, что у пациентов с ГЭРБ в сочетании с СОАГС повышение интенсивности экспрессии MTNR1B ассоциировано со степенью тяжести апноэ. Выявленные у данной категории пациентов особенности экспрессии могут свидетельствовать о снижении чувствительности рецепторов МТNR1B, обусловленном хронической гипоксией, характерной для апноэ во сне.

The aim of the present research was to assess the expression of melatonin receptors (MTNR1B) in the esophageal mucosa in the gastroesophageal reflux disease associated with obstructive sleep apnea/hypopnea syndrome and to study the relationship between the detected changes and the sleep apnea severity. 84 patients aged 30–60 years, including those with gastroesophageal reflux disease (group 1, n  =  25), those with gastroesophageal reflux disease associated with sleep apnea/hypopnea (group 2, n = 23), those with obstructive sleep apnoe/ hypopnoe syndrome (group 3, n = 18), and almost healthy people (group 4, n = 18), were studied. Diagnoses were based on endoscopic imaging and respiratory monitoring. The MTNR1B expression in the esophageal mucosa was determined by the immunohistochemical method using specific antibodies. The MTNR1 B expression was evaluated quantitatively using the computer program Aperio ImageScope _v9.1.19.1567. The obtained material was analyzed statistically using the software Statistica 10.0. The group 2 patients were shown to have a higher MTNR1B expression compared to the group 1 patients (0.122 [0.064; 0.266] versus 0.620 [0.332; 0.983]; p =  0.00001) and the group 3 patients (0.620 [0.332; 0.983] versus 0.232 [0.120; 0.418]; р = 0.0098). The MTNR1 B expression increased with growing sleep apnea severity: it is 0.295 [0.198; 0.403] in patients with mild apnea versus 0.941 [0.345; 0.992] in patients with moderate and severe apnea (p = 0.0021). A direct correlation between the MTNR1B expression and the sleep apnea severity degree (r = 0.50; р = 0.0016) was revealed. Patients with gastroesophageal reflux disease combined with sleep apnea revealed an increase in the MTNR1 B expression associated with the apnea severity. The revealed features of the MTNR1 B expression secondary to esophageal mucosal damage indicate the MTNR1 B inactivation secondary to accompanying apnea of hypoxia.

рецептор мелатонинаMTNR1 Bэкспрессия рецепторовмелатонин6-сульфатоксимелатонингастроэзофагеальная рефлюксная болезньсиндром обструктивного апноэ/гипопноэ снаmelatonin receptorsMTNR1Bexpression of receptorsmelatonin6-sulfatoxymelatoningastroesophageal reflux diseaseobstructive sleep apnea/hypopnea syndromeReferencesEstimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis / A. V. Benjafield [et al.] // Lancet Respir. Med. – 2019. – Vol. 7, N 8. – P. 687–698. https://doi.org/10.1016/S2213-2600(19)30198-5A. V. Benjafield, N. T. Ayas, P. R. Eastwood, R. Heinzer, Ip M. S. M., Morrell M. J. [et al.]. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respiratory Medicine, 2019, vol. 7, no. 8, pp. 687–698. https://doi.org/10.1016/S2213-2600(19)30198-5Gastroesophageal reflux disease is associated with high risk of obstructive sleep apnea syndrome / Y. Chen [et al.] // Chinese J. Inter. Med. – 2018. – Vol. 57, N 11. – P. 824–829. https://doi.org/10.3760/cma.j.issn.0578-1426.2018.11.006Chen Y., Xiong L., Zeng J., Wei Y. G. Gastroesophageal reflux disease is associated with high risk of obstructive sleep apnea syndrome. Chinese Journal of Internal Medicine, 2018, vol. 57, no. 11, pp. 824–829. https://doi.org/10.3760/cma.j.issn.0578-1426.2018.11.006Карпович, О. А. Диагностическое значение мелатонина в выявлении синдрома обструктивного апноэ/гипопноэ сна у пациентов с гастроэзофагеальной рефлюксной болезнью / О. А. Карпович // Мед. новости. – 2019. – № 12. – С. 49–53.Karpovich O. A. The diagnostic role of melatonin in detection of obstructive sleep apnea/hypopnea syndrome in patients with gastroesophageal reflux disease. Meditsinskie novosti [Medical news], 2019, no. 12, pp. 49–53 (in Russian).Effect of CPAP therapy on symptoms of nocturnal gastroesophageal reflux among patients with obstructive sleep apnea / S. Tamanna [et al.] // J. Clin. Sleep Med. – 2016. – Vol. 12, N 9. – P. 1257–1261. https://doi.org/10.5664/jcsm.6126Tamanna S., Campbell D., Warren R., Ullah M. I. Effect of CPAP therapy on symptoms of nocturnal gastroesophageal reflux among patients with obstructive sleep apnea. Journal of Clinical Sleep Medicine, 2016, vol. 12, no. 9, pp. 1257–1261. https://doi.org/10.5664/jcsm.6126Independent association of obstructive sleep apnea with Barrett’s esophagus / Y. B. Hadi [et al.] // J. Gastroenterol. Hepatol. – 2019. – Vol. 35, N 3. – P. 408–411. https://doi.org/10.1111/jgh.14779Hadi Y. B., Khan A. A., Naqvi S. F. Z., Kupec J. T. Independent association of obstructive sleep apnea with Barrett’s esophagus. Journal of Gastroenterology and Hepatology, 2019, vol. 35, no. 3, pp. 408–411. https://doi.org/10.1111/jgh.14779Bubenik, G. Thirty four years since the discovery of gastrointestinal melatonin / G. Bubenik // J. Physiol. Pharmacol. – 2008. – Vol. 59, suppl. 2. – Р. 33–51.Bubenik G. Thirty four years since the discovery of gastrointestinal melatonin. Journal of Physiology and Pharmacology, 2008, vol. 59, suppl. 2, pp. 33–51.Sommansson, A. Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptordependent pathway in rats in vivо / A. Sommansson, O. Nylander, M. Sjöblom // J. Pineal Res. – 2013. – Vol. 54, N 3. – Р. 282–291. https://doi.org/10.1111/jpi.12013Sommansson A., Nylander O., Sjöblom V. Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivо. Journal of Pineal Research, 2013, vol. 54, no. 3, pp. 282–291. https://doi.org/10.1111/jpi.12013Melatonin inhibits il-1β-induced monolayer permeability of human umbilical vein endothelial cells via rac activation / X. Yuan [et al.] // J. Pineal Res. – 2011. – Vol. 51, N 2. – Р. 220–225. https://doi.org/10.1111/j.1600-079X.2011.00882.xYuan X., Li B., Li H., Xiu R. Melatonin inhibits il-1β-induced monolayer permeability of human umbilical vein endothelial cells via rac activation. Journal of Pineal Research, 2011, vol. 51, no. 2, pp. 220–225. https://doi.org/10.1111/j.1600-079X.2011.00882.xМелатонин: перспективы применения в клинике / под ред. С. И. Рапопорта. – М. : ИМА-ПРЕСС, 2012. – 175 с.Rapoport S. I. (ed.). Melatonin: prospects for use in the clinic. Moscow, IMA-PRESS Publ., 2012. 175 p. (in Russian).Amaral, F. A brief review about melatonin, a pineal hormone / F. Amaral, J. Cipolla-Neto // Arch. Endocrinol. Metab. – 2018. – Vol. 62, N 4. – Р. 472–479. http://dx.doi.org/10.20945/2359-3997000000066Amaral F. J., Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Archives of Endocrinology Metabolism, 2018, vol. 62, no. 4, pp. 472–479. http://dx.doi.org/10.20945/2359-3997000000066Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP / C. Hernandez [et al.] // Eur. Respir. J. – 2007. – Vol. 30, N 3. – Р. 496–500. https://doi.org/10.1183/09031936.00051906Hernandez C., Abreu J., Abreu P., Castro A., Jimenez A. Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP. European Respiratory Journal, 2007, vol. 30, no. 3, pp. 496–500. https://doi.org/10.1183/09031936.00051906Diurnal and nocturnal serum melatonin concentrations after treatment with continuous positive airway pressure in patients with obstructive sleep apnea / M. Barnaś [et al.] // Polish Arch. Int. Med. – 2017. – Vol. 127, N 9. – Р. 589–596. https://doi.org/10.20452/pamw.4062Barnaś M., Maskey-Warzęchowska M., Bielicki P., Kumor M., Chazan R. Diurnal and nocturnal serum melatonin concentrations after treatment with continuous positive airway pressure in patients with obstructive sleep apnea. Polish Archives of Internal Medicine, 2017, vol. 127, no. 9, pp. 589–596. https://doi.org/10.20452/pamw.4062Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease / I. Brzozowska [et al.] // Curr. Pharm. Design. – 2014. – Vol. 20, N 30. – Р. 4807–4815. https://doi.org/10.2174/1381612819666131119110258Brzozowska I., Strzalka M., Drozdowicz D., Konturek S. J., Brzozowski T. Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease. Current Pharmaceutical Design, 2014, vol. 20, no. 30, pp. 4807–4815. https://doi.org/10.2174/1381612819666131119110258The montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus / M.D.NimishVakil[etal.]//Am.J.Gastroenterol.–2006.–Vol.101,N8.–P.1900–1920. https://doi.org/10.1111/j.1572-0241.2006.00630.xNimish Vakil M. D., van Zanten S. V., Kahrilas P., Dent J., R. Jones. The montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. American Journal of Gastroenterology, 2006, vol. 101, no. 8, pp. 1900–1920. https://doi.org/10.1111/j.1572-0241.2006.00630.xКарпович, О. А. Особенности суточной секреции мелатонина у пациентов с гастроэзофагеальной рефлюксной болезнью, ассоциированной с синдромом обструктивного апноэ/гипопноэ сна / О. А. Карпович, В. И. Шишко, В. Р. Шулика // Казан. мед. журн. – 2019. – Т. 100, № 5. – C. 762–768.Karpovich O. A., Shishko V. I., Shulika V. R. The particuliarities of melatonin daily production by patients with gastroesophageal reflux disease associated with obstructive apnea/hypopnea sleep syndrome. Kazanskii meditsinskii zhurnal [Kazan medical journal], 2019, vol. 100, no. 5, pp. 762–768 (in Russian).Щербенков, И. М. Особенности нарушения микроциркуляции при гастроэзофагеальной рефлюксной болезни : дис. … кандидат медицинских наук : 14.00.05 / И. М. Щербенков. – М., 2006. – 136 л.Shcherbenkov I. M. Features of microcirculatory disorders in gastroesophageal reflux disease. Ph. D. Thesis. Moscow, 2006. 136 p. (in Russian).Expression of MT2 receptor in patients with gastric adenocarcinoma and its relationship with clinicopathological features / N. N. Nasrabadi [et al.] // J. Gastrointest. Cancer. – 2014. – Vol. 45, N 1. – Р. 54–60. https://doi.org/10.1007/s12029-013-9552-0Nasrabadi N. N., Ataee R., Abediankenari S., Shokrzadeh M., Najafi M., Hoseini S. V., Haghi H., Jan A. Expression of MT2 receptor in patients with gastric adenocarcinoma and its relationship with clinicopathological features. Journal of Gastrointestinal Cancer, 2014, vol. 45, no. 1, pp. 54–60. https://doi.org/10.1007/s12029-013-9552-0

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