pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2018-28-2-169-176pulmo-982Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESПротивовоспалительный и регенеративный эффект подавления гипоксийного сигналинга на модели хронической обструктивной болезни легкихAnti-inflammatory and regenerative effects of hypoxic signaling inhibition in a model of COPDТитоваО. Н.TitovaO. N.

д. м. н., директор Научно-исследовательского института пульмонологии

titova-on@mail.ruКузубоваН. А.KuzubovaO. N.

д. м. н., заместитель директора Научно-исследовательского института пульмонологии

kuzubova@mail.ruЛебедеваЕ. С.LebedevaE. S.

к. б. н., ведущий научный сотрудник Научно-исследовательского института пульмонологии

osmelena@mail.ruСурковаЕ. А.SurkovaE. A.

к. б. н., старший научный сотрудник Научно-методического центра по молекулярной медицине

easurkova@mail.ruПреображенскаяТ. Н.PreobrazhenskayaT. N.

к. б. н., доцент Федерального государственного бюджетного военного образовательного учреждения высшего образования «Военно-медицинская академия имени С.М.Кирова» Министерства обороны Российской Федерации, доцент Федерального государственного бюджетного образовательного учреждения высшего образования «Санкт-Петербургский государственный университет» Министерства образования и науки Российской Федерации

tanapp@yandex.ruДвораковскаяИ. В.DvorakovskayaI. V.

д. м. н., ведущий научный сотрудник Научно-исследовательского института пульмонологии

i_dvorakovskaya@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П.Павлова» Министерства здравоохранения Российской ФедерацииРоссияAcademician I.P.Pavlov Federal First Saint-Petersburg State Medical University, Healthcare Ministry of RussiaRussian FederationФедеральное государственное бюджетное военное образовательное учреждение высшего образования «Военно-медицинская академия имени С. М. Кирова» Министерства обороны Российской Федерации; Федеральное государственное бюджетное образовательное учреждение высшего образования «Санкт-Петербургский государственный университет»РоссияS.M.Kirov Federal Military Medical Academy, Ministry of Defense of Russian Federation, Saint-Petersburg; Saint-Petersburg Federal State UniversityRussian Federation201830062018282169176Copyright © Титова О.Н., Кузубова Н.А., Лебедева Е.С., Суркова Е.А., Преображенская Т.Н., Двораковская И.В., 20182018Титова О.Н., Кузубова Н.А., Лебедева Е.С., Суркова Е.А., Преображенская Т.Н., Двораковская И.В.Titova O.N., Kuzubova O.N., Lebedeva E.S., Surkova E.A., Preobrazhenskaya T.N., Dvorakovskaya I.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/982

Цель. Оценка противовоспалительного и регенеративного эффекта предотвращения активации гипоксийного сигналинга на модели хронической обструктивной болезни легких (ХОБЛ) путем ингибирования циклооксигеназы-2 (СОХ-2)-зависимого провоспалительного каскада. Материалы и методы. При помощи экспозиций диоксидом азота (NO2, 30–40 мг / м3) в течение 90 дней у крыс создана модель ХОБЛ. В качестве ингибитора СОХ-2 применялся целекоксиб. С 30-го дня крысам 1-й группы через пищеводный зонд вводился целекоксиб (25 мг / кг); животные 2-й группы (контроль) получали 0,9%-ный NaCl. Интактные крысы составили 3-ю группу. Животные выводились из опыта после 60 и 90 дней экспозиции NO2 путем цервикальной дислокации. При этом выполнялась цитография бронхоальвеолярной лаважной жидкости (БАЛЖ), определялось содержание COX-2, гипоксия-индуцибельного фактора-1a (HIF-1a), интерлейкина (IL)-17, сурфактантного протеина D (SP-D) методом ELISA. Выполнено гистологическое исследование легочной ткани. Результаты. Показано, что после 90-дневной экспозиции NO2 в БАЛЖ контрольных особей содержание нейтрофилов в 7,7 раза превышало интактное значение. Достоверно возрастало содержание провоспалительных медиаторов СОХ-2, HIF-1α, IL-17, а уровень SP-D снижался. Применение целекоксиба сопровождалось нормализацией цитологического профиля БАЛЖ и уменьшением содержания СОХ-2, HIF-1α, IL-17, что свидетельствовало о снижении активности гипоксийного сигналинга и воспалительного процесса. Значительно возрастала концентрация SP-D, что можно рассматривать как следствие восстановления морфологической структуры бронхоальвеолярного эпителия, о чем свидетельствовали данные гистологического исследования легочной ткани. Заключение. При ингибировании СОХ-2 отмечен супрессивный эффект на HIF-1α-сигналинг и уменьшение легочного воспаления. Полученные результаты подтверждают функционально-регуляторную связь HIF-1α и СОХ-2-сигнальных каскадов, которая может быть терапевтической мишенью для предотвращения прогрессирования воспаления и ремоделирования дыхательных путей при ХОБЛ.

The aim of this study was to investigate anti-inflammatory and regenerative effects of inhibited activation of hypoxic signaling in COPD model using cyclooxygenase-2 (COX-2)-dependent pro-inflammatory cascade inhibition. Methods. COPD was modelled in rats by nitrogen dioxide (NO2, 30-40 mg×m–3) exposure for 90 days. Celecoxib was used as COX-2 inhibitor. The study group rats were given celecoxib (25 mg×kg–1) through an esophageal probe after 30 days of exposure. Control rats were given saline solution. The group 3 rats were intact. The rats were put out of the experience using cervical dislocation after 60 and 90 days of NO2 exposure. Bronchoalveolar lavage fluid (BALF) cytology was analyzed. COX-2, hypoxia-inducible factor-1α (HIF-1α), interleukin-17 (IL-17), and surfactant protein D (SP-D) were measured in BALF using ELISA method. Histological examination of the lung tissue was also performed. Results. 90-day exposure of NO2 resulted in 7.7-fold increase in BALF neutrophil count compared to that in intact rats. Pro-inflammatory mediators (СOX-2, HIF-1α, and IL-17) significantly increased and SP-D level decreased in BALF. Administration of celecoxib was accompanied by normalization of BALF cytology profile and decrease in COX-2, HIF-1α, and IL-17 levels in BALF; this could indicate a reduction in the hypoxic signaling activity and in inflammation. The growth of SP-D concentration could be considered as a result of the alveolar epithelium restoration. This was confirmed by histological examination of the lung tissue. Conclusion. COX-2 inhibition suppressed HIF-1α-signaling and decreased the lung inflammation. The results confirm a functional and regulatory relationship between HIF-1α and COX-2 signaling cascades that could be a therapeutic target for preventing the progression of inflammation and airway remodeling in COPD.

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