cfpdБюллетень физиологии и патологии дыханияBulletin Physiology and Pathology of Respiration1998-5029Дальневосточный научный центр физиологии и патологии дыхания10.36604/1998-5029-2025-97-8-24cfpd-1267Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHАнализ ранних молекулярных изменений, ассоциированных с ХОБЛ, путем транскриптомного профилирования клеток A549 в эксперименте in vitroAnalysis of early molecular changes associated with COPD via transcriptomic profiling of A549 cells in an in vitro experimentНаумовД. Е.NaumovD. E.

Денис Евгеньевич Наумов, канд. мед. наук, зав. лабораторией молекулярных и трансляционных исследований

675000, г. Благовещенск, ул. Калинина, 22

Denis E. Naumov, PhD (Med.), Head of Laboratory of Molecular and Translational Research

22 Kalinina Str., Blagoveshchensk, 675000

denn1985@bk.ruКотоваО. О.KotovaO. O.

Олеся Олеговна Котова, канд. мед. наук, старший научный сотрудник, лаборатория механизмов вирус-ассоциированных патологий развития

675000, г. Благовещенск, ул. Калинина, 22

Olesya O. Kotova, PhD (Med.), Senior Staff Scientist, Laboratory of Mechanisms of Virus-Associated Developmental Pathology

22 Kalinina Str., Blagoveshchensk, 675000

foxy_voxy_on@mail.ruГассанД. А.GassanD. A.

Дина Анатольевна Гассан, канд. мед. наук, зав. лабораторией механизмов вирус-ассоциированных патологий развития

675000, г. Благовещенск, ул. Калинина, 22

Dina A. Gassan, PhD (Med.), Head of Laboratory of Mechanisms of Virus-Associated Developmental Pathology

22 Kalinina Str., Blagoveshchensk, 675000

danishi@mail.ruСугайлоИ. Ю.SugayloI. Yu.

Ивана Юрьевна Сугайло, канд. мед. наук, научный сотрудник, лаборатория молекулярных и трансляционных исследований

675000, г. Благовещенск, ул. Калинина, 22

Ivana Yu. Sugaylo, PhD (Med.), Staff Scientist, Laboratory of Molecular and Translational Research

22 Kalinina Str., Blagoveshchensk, 675000

ivanka_888@mail.ruФедеральное государственное бюджетное научное учреждение «Дальневосточный научный центр физиологии и патологии дыхания»Far Eastern Scientific Center of Physiology and Pathology of Respiration202521092025097824Copyright © Наумов Д.Е., Котова О.О., Гассан Д.А., Сугайло И.Ю., 20252025Наумов Д.Е., Котова О.О., Гассан Д.А., Сугайло И.Ю.Naumov D.E., Kotova O.O., Gassan D.A., Sugaylo I.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cfpd.elpub.ru/jour/article/view/1267

Введение. Хроническая обструктивная болезнь легких (ХОБЛ) – распространенное заболевание с высокой социальной значимостью, в патогенезе которого существенную роль может играть реакция альвеолярного эпителия на сигаретный дым.Цель. Комплексная характеристика транскриптомных изменений в клетках A549, возникающих в ответ на действие экстракта сигаретного дыма (ЭСД), включая анализ дифференциальной экспрессии генов и ключевых сигнальных путей, с оценкой их потенциальной роли в развитии патологического процесса при ХОБЛ.Материалы и методы. Клетки A549 выращивали в среде DMEM до 80% конфлюэнтности, а затем инкубировали с 5% ЭСД или в контрольных условиях в течение 24 часов (n = 3 на каждое условие). Выделенную тотальную РНК подвергали обогащению для получения мРНК. Секвенирование выполняли на секвенаторе MGISEQ-200 в режиме SE50. Обработка данных включала картирование прочтений (Salmon), анализ дифференциальной экспрессии (DESeq2) и функционального обогащения генов (Cytoscape).Результаты. Действие ЭСД сопровождалось признаками дезорганизации актинового цитоскелета (ингибирование Rho ГТФаз, даунрегуляция ACTB) и стресса эндоплазматического ретикулума с парадоксальной активацией mTORC1 сигналинга на фоне подавления транскрипции, пролиферации и апоптоза, что в совокупности может быть охарактеризовано как метаболически активный клеточный стазис. Одновременно с этим отмечалось усиление протеасомной деградации и антигенной презентации собственных, вероятно, дефектных белков с целью стимуляции иммунологического надзора. В то время как провоспалительный сигналинг, в целом, был ослаблен, увеличивалась экспрессия IL1A, SPP1 и CSF3, что может способствовать привлечению и активации нейтрофилов, макрофагов и моноцитов in vivo. Предполагаемые нарушения эффероцитоза (за счет апрегуляции ANXA5) и индукции апоптоза цитотоксическими T-клетками (вследствие нарушения эндоцитоза гранзимов и ингибирования каспаз) могут приводить к формированию хронического воспаления с аутоиммунным компонентом.Заключение. Активация mTORC1 сигналинга и презентации аутоантигенов на фоне стресса эндоплазматического ретикулума, а также потенциальное снижение способности цитотоксических T-клеток вызывать апоптоз, может являться ключевыми механизмами патогенеза ХОБЛ, опосредующими повреждение альвеолярного эпителия под действием сигаретного дыма.

Introduction. Chronic obstructive pulmonary disease (COPD) is a common condition of high social importance, in which the response of alveolar epithelium to cigarette smoke may play a critical role in disease pathogenesis.Aim. To comprehensively characterize transcriptomic alterations in A549 cells in response to cigarette smoke extract (CSE), including differential gene expression and key signaling pathways, and to evaluate their potential contribution to pathological processes associated with COPD.Materials and methods. A549 cells were cultured in DMEM until reaching 80% confluency, then incubated with 5% CSE or maintained under control conditions for 24 hours (n = 3 per group). Total RNA was extracted and enriched for mRNA. Sequencing was performed on the MGISEQ-200 platform in SE50 mode. Data analysis included read mapping (Salmon), differential gene expression analysis (DESeq2), and functional enrichment (Cytoscape).Results. CSE exposure was associated with signs of actin cytoskeleton disorganization (Rho GTPase inhibition, ACTB downregulation) and endoplasmic reticulum stress, along with paradoxical activation of mTORC1 signaling amid suppression of transcription, proliferation, and apoptosis – a combination that may represent a state of metabolically active cellular stasis. Concomitantly, proteasomal degradation and antigen presentation of likely defective self-proteins were enhanced, possibly promoting immune surveillance. While proinflammatory signaling was generally attenuated, increased expression of IL1A, SPP1 and CSF3 may facilitate recruitment and activation of neutrophils, macrophages, and monocytes. Impaired efferocytosis (via upregulation of ANXA5) and defective apoptosis induction by cytotoxic T cells (due to disrupted granzyme endocytosis and inhibition of caspases) may lead to persistent inflammation with an autoimmune component.Conclusion. Activation of mTORC1 signaling and autoantigen presentation under endoplasmic reticulum stress, as well as a potential reduction in the ability of cytotoxic T cells to induce apoptosis, may represent key pathogenic mechanisms of COPD, mediating alveolar epithelial injury induced by cigarette smoke.

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