Cell and Tissue BiologyCell and Tissue BiologyЦитология0041-37713034-6061The Russian Academy of Sciences66966110.31857/S0041377123010091GLDCGDArticlesСтатьиThe Role of the Notch Signaling Pathway in the Pathogenesis of Lung Diseases of Non-infectious EtiologyРоль сигнального пути NOTCH в патогенезе заболеваний легких неинфекционной этиологииSerebryakovaV. A.СеребряковаВ. А.serebryakova-val@mail.ruSaninaA. E.СанинаА. Е.serebryakova-val@mail.ruUrazovaO. I.УразоваО. И.serebryakova-val@mail.ruGadzhievA. A.ГаджиевА. А.serebryakova-val@mail.ruStepanovaE. P.СтепановаЕ. П.serebryakova-val@mail.ruPharmacology Department of Siberian State Medical UniversityКафедра фармакологии Сибирского государственного медицинского университетаPathophysiology Department of Siberian State Medical UniversityКафедра патофизиологии Сибирского государственного медицинского университетаTomsk State University of Control Systems and RadioelectronicsТомский государственный университет систем управления и радиоэлектроникиTomsk Phthisiopulmonological Medical CenterТомский фтизиопульмонологический медицинский центрru01012023202365131027022025Received:27022025Published:01012023Copyright ©; 2023, В.А. Серебрякова, А.Е. Санина, О.И. Уразова, А.А. Гаджиев, Е.П. СтепановаCopyright ©; 2023, В.А. Серебрякова, А.Е. Санина, О.И. Уразова, А.А. Гаджиев, Е.П. Степанова2023В.А. Серебрякова, А.Е. Санина, О.И. Уразова, А.А. Гаджиев, Е.П. СтепановаВ.А. Серебрякова, А.Е. Санина, О.И. Уразова, А.А. Гаджиев, Е.П. Степановаhttps://journals.eco-vector.com/0041-3771/article/view/669661

A review of current literature data on the significance of the Notch signaling pathway in the mechanisms of the development of diseases of the respiratory system – chronic obstructive pulmonary disease (COPD), bronchial asthma (BA) and lung cancer is presented. In studies of lung tissue samples of patients with COPD and lung tissues of mice, it was found that activation of the Notch signaling pathway promotes metaplasia and increases the functional activity of goblet cells, protects epithelial cells from apoptosis and oxidative stress. Suppression of the Notch−Jagged1/Jagged2 pathway is associated with the transdifferentiation of club-shaped cells into ciliated ones. In patients with AD, the Notch signaling pathway promotes differentiation of Th2 lymphocytes. In the ovalbumin-induced bronchial asthma model, the Notch cascade increases the imbalance of Th17/Treg lymphocyte populations, the production of IL-4, IL-5, IL-13, IL-17, the formation of allergen-specific IgE, eosinophilic infiltration and metaplasia of goblet-shaped epithelial cells of the respiratory tract. A decrease in the concentration of IgE, Th2-type cytokines (IL-4, IL‑5, IL-13), an increase in the number of Treg cells and the level of TGFß in bronchoalveolar lavage in mice with asthma, mediated by the introduction of dendritic cells expressing the ligands DLL1 and Jagged1, indicates the protective role of the Notch signaling pathway. On samples of tumor tissue and cell lines of non-small cell lung cancer, it was found that an increase in the expression of Notch-1 and Notch-3 mRNA is associated with increased proliferative activity, malignant cell transformation, a high risk of metastasis to lymph nodes and an unfavorable prognosis of the disease. In the samples of tumor tissue of small cell lung cancer, an increase in the expression of the Notch ligand DLK1 signaling inhibitor gene, the Ascl1 transcription factor gene and lysine-specific histone demethylase 1 (LSD1) was recorded. Suppression of LSD1 activity is accompanied by reactivation of signaling via Notch-1 receptor and subsequent inhibition of the transcription factor Ascl1, which induces the initial stages of tumor transformation.

Представлен обзор современных данных литературы о значении сигнального пути Notch в механизмах развития заболеваний респираторной системы – хронической обструктивной болезни легких (ХОБЛ), бронхиальной астмы (БА) и рака легкого. В исследованиях образцов тканей легких больных с ХОБЛ и тканей легких мышей установлено, что активация сигнального пути Notch способствует метаплазии и повышению функциональной активности бокаловидных клеток, защищает эпителиальные клетки от апоптоза и окислительного стресса. Подавление пути Notch–Jagged1/Jagged2 ассоциировано с трансдифференцировкой булавовидных клеток в ресничатые. У больных БА сигнальный путь Notch способствует дифференцировке Тh2-лимфоцитов. В модели бронхиальной астмы, индуцированной овальбумином, каскад Notch увеличивает дисбаланс популяций лимфоцитов Th17/Treg, продукцию IL-4, IL-5, IL-13, IL-17, образование аллерген-специфических IgE, эозинофильную инфильтрацию и метаплазию бокаловидных клеток эпителия дыхательных путей. Снижение концентрации IgE, цитокинов типа Th2 (IL-4, IL-5, IL-13), увеличение числа Treg-клеток и уровня TGFβ в бронхоальвеолярном лаваже у мышей с астмой, опосредованное введением дендритных клеток, экспрессирующих лиганды DLL1 и Jagged1, свидетельствует о протективной роли сигнального пути Notch. На образцах опухолевой ткани и линии клеток немелкоклеточного рака легкого установлено, что увеличение экспрессии мРНК Notch-1 и Notch-3 связано с повышением пролиферативной активности, злокачественной трансформацией клеток, высоким риском метастазирования в лимфатические узлы и неблагоприятным прогнозом заболевания. В образцах опухолевой ткани мелкоклеточного рака легкого регистрируется повышение экспрессии гена ингибитора передачи сигналов Notch – лиганда DLK1, гена фактора транскрипции Ascl1 и лизин-специфической гистондеметилазы 1 (LSD1). Подавление активности LSD1 сопровождается реактивацией передачи сигналов через Notch-1-рецептор и последующим угнетением фактора транскрипции Ascl1, индуцирующего начальные стадии опухолевой трансформации.

Notchchronic obstructive pulmonary diseasebronchial asthmalung cancerNotchхроническая обструктивная болезнь легкихбронхиальная астмарак легкогоИшутина О.В. 2021. Сурфактантная система лeгких. Обзорная статья. Вестник ВГМУ. Т. 20. № 4. С. 7. https://doi.org/ (Ishutsina O.V. 2021. The surfactant system of the lungs. A review article. Vestnik VGMU Т. 20. № 4. С. 7. https://doi.org/10.22263/2312-4156.2021.4.7)Целуйко С.С., Намаконова В.С., Красавина Н.П., Чжоу С.Д., Ли Ц. 2014. Идентификация и локализация стволовых клеток в органах дыхательной системы (обзор литературы). Бюллетень физиологии и патологии дыхания. № 52. С. 121. (Tseluyko S.S., Namakonova V.S., Krasavina N.P., Zhou X., Li Q. 2014. Identification and localization of stem cells in the respiratory system (review). Bulletin Physiology and Pathology of Respiration. V. 52. P. 121).Agustí A., Vogelmeier C., Faner R. 2020. COPD 2020: changes and challenges. Am. J. Physiol. Lung Cell. Mol. Physiol. V. 319. P. L879. https://doi.org/10.1152/ajplung.00429.2020Augert A., Eastwood E., Ibrahim A.H., Wu N., Grunblatt E., Basom R., Liggitt D., Eaton K.D., Martins R., Poirier J.T., Rudin C.M., Milletti F., Cheng W.Y., Mack F., MacPherson D. et al. 2019. Targeting NOTCH activation in small cell lungcancer through LSD1 inhibition. Sci. Signal. V. 12. P. 2922. https://doi.org/10.1126/scisignal.aau2922Bagdonas E., Raudoniute J., Bruzauskaite I., Aldonyte R. 2015. Novel aspects of pathogenesis and regeneration mechanisms in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. V. 10. P. 995. https://doi.org/ d.s82518https://doi.org/10.2147/copBaumgart A., Seidl S., Vlachu P., Michel L., Mitova N., Schatz N., Specht K., Koch I., Schuster T., Grundler R., Kremer M., Fend F., Siweke J.T., Peschel S., Duister J. et al. 2010. ADAM17 regulates the expression of the epidermal growth factor receptor by activating Notch1 extra-small cell lung cancer. Cancer Res. V. 70. P. 5368. https://doi.org/10.1158/0008-5472Boucherat O., Chakir J., Jeannotte L. 2012. The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways. Biol. Open. V. 1. P. 677. https://doi.org/10.1242/bio.20121701Cai W.X., Liang L., Wang L., Han J.T., Zhu X.X., Han H., Hu D.H., Zhang P. 2014. Inhibition of Notch signaling leads to increased intracellular ROS by up-regulating Nox4 expression in primary HUVECs. Cell Immunol. V. 287. P. 129. https://doi.org/10.1016/j.cellimm.2013.12.009Chen C.Y., Chen Y.Y., Hsieh M.S., Ho C.C., Chen K.Y., Shih J.Y., Yu C.J. 2017. Expression of Notch Gene and Its Impact on Survival of Patients with Resectable Non-small Cell Lung Cancer. J. Cancer. V. 8. P. 1292. https://doi.org/10.7150/jca.17741Chen Y., Jie V., Yan V., Zhou K., Xiao Y. 2012. Lysine-specific histone demethylase 1 (LSD1): a potential molecular target for tumor therapy. Crit. Rev. Eukaryotic Gene Expression. V. 22. P. 53. https://doi.org/10.1615/critreveukargeneexpr.v22.i1.40Galluzzo P., Bocchetta M. 2011. Notch signaling in lung cancer. Expert Rev. Anticancer Ther. V. 11. P. 533. https://doi.org/10.1586/era.10.158George J., Lim J.S., Chan S.J., Kun W., Ozretic L., Kong G., Lenders F., Lu H., Fernandez-Cuesta L., Bosco G., Muller S., Damen I., Yahchan N.S., Park K.S., Yang D. et al. 2015. Complex genomic profiles of small cell lung cancer. Nature. V. 524. P. 47. https://doi.org/10.1038/nature14664He Z., Wu J., Zeng X., Bao H., Liu X. 2021. Role of the Notch ligands Jagged1 and Delta4 in Th17/Treg immune imbalance in a mouse model of chronic asthma. Exp. Lung Res. V. 47. P. 289. https://doi.org/10.1080/01902148.2021.1933653Hua S., Liu F., Wang M. 2019. Emodin Alleviates the Airway Inflammation of Cough Variant Asthma in Mice by Regulating the Notch Pathway. Med. Sci. Monit. V. 25. P. 5621. https://doi.org/10.12659/MSM.915080Huang M.T., Chiu C.J., Chiang B.L. 2019. Multi-Faceted Notch in Allergic Airway Inflammation. Int. J. Mol. Sci. V. 20. P. 3508. https://doi.org/10.3390/ijms20143508Huang Q., Han L., Lv R., Ling L. 2019. Magnolol exerts anti-asthmatic effects by regulating Janus kinase-signal transduction and activation of transcription and Notch signaling pathways and modulating Th1/Th2/Th17 cytokines in ovalbumin-sensitized asthmatic mice. Korean J. Physiol. Pharmacol. V. 23. P. 251. https://doi.org/10.4196/kjpp.2019.23.4.251Kared H., Adle-Biassette H., Foïs E., Masson A., Bach J., Chatenoud L. 2006. Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. Immunity. V. 25. 823. https://doi.org/10.1016/j.immuni.2006.09.008Katoh M., Katoh M. 2020. Precision medicine for the treatment of human cancer with impaired regulation of Notch signal transmission (review). Int. J. Mol. Med. V. 45. P. 279. https://doi.org/10.3892/ijmm.2019.4418Kiyokawa H., Morimoto M. 2020. Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease. Dev. Growth Differ. V. 62. P. 67. https://doi.org/10.1111/dgd.12628Lee C.C., Lin C.L., Leu S.J., Lee Y.L. 2018. Overexpression of Notch ligand Delta-like-1 by dendritic cells enhances their immunoregulatory capacity and exerts antiallergic effects on Th2-mediated allergic asthma in mice. Clin. Immunol. V. 187. P. 58. https://doi.org/10.1016/j.clim.2017.10.005Leonetti A., Facchinetti F., Minari R., Cortellini A., Rolfo K.D., Giovannetti E., Tiseo M. 2019. The Notch pathway in small cell lung cancer: from preclinical data to therapeutic problems. Cell. Oncol. (Dordr). V. 42. P. 261. https://doi.org/10.1007/s13402-019-00441-3Lim J.S., Ibaseta A., Fischer M.M., Cancilla B., O’Young G., Cristea S., Luca V.C., Yang D., Jahchan N.S., Hamard C., Antoine M., Wislez M., Kong C., Cain J., Liu Y.W. et al. 2017. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature. V. 545. P. 360. https://doi.org/10.1038/nature22323Limbourg F.P., Takeshita K., Radtke F., Bronson R.T., Chin M.T., Liao J.K. 2005. Essential role of endothelial Notch1 in angiogenesis. Circulation. V. 111. P. 1826. https://doi.org/10.1161/01.CIR.0000160870.93058.DDLin C.L., Huang H.M., Hsieh C.L., Fan C.K., Lee Y.L. 2019. Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice. Immunology. V. 156. P. 199. https://doi.org/10.1111/imm.13021Luo J., Li L., Hu D., Zhang X. 2020. LINC00612/miR-31-5p/Notch1 Axis Regulates Apoptosis, Inflammation, and Oxidative Stress in Human Pulmonary Microvascular Endothelial Cells Induced by Cigarette Smoke Extract. Int. J. Chron. Obstruct. Pulmon. Dis. V. 15. P. 2049. https://doi.org/10.2147/COPD.S255696Ma J., Rubin B.K., Voynow J.A. 2018. Mucins, Mucus, and Goblet Cells. Chest. V. 154. P. 169. https://doi.org/10.1016/j.chest.2017.11.008Morianos I., Semitekolou M. 2020. Dendritic Cells: Critical Regulators of Allergic Asthma. Int. J. Mol. Sci. V. 21. P. 7930. https://doi.org/10.3390/ijms21217930Morimoto M., Liu Z., Cheng H.T., Winters N., Bader D., Kopan R. 2010. Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate. J. Cell. Sci. V. 123. P. 213. https://doi.org/10.1242/jcs.058669Motooka Y., Fujino K., Sato Y., Kudoh S., Suzuki M., Ito T. 2017. Pathobiology of Notch2 in lung cancer. Pathology. V. 49. P. 486. https://doi.org/10.1016/j.pathol.2017.05.005Nie Y., Yang B., Hu J., Zhang L., Ma Z. 2021. Bruceine D ameliorates the balance of Th1/Th2 in a mouse model of ovalbumin-induced allergic asthma via inhibiting the NOTCH pathway. Allergol. Immunopathol. (Madr). V. 49. P. 73. https://doi.org/10.15586/aei.v49i6.499Ostedgaard L.S., Moninger T.O., McMenimen J.D., Sawin N.M., Parker C.P., Thornell I.M., Powers L.S., Gansemer N.D., Bouzek D.C., Cook D.P., Meyerholz D.K., Abou Alaiwa M.H., Stoltz D.A., Welsh M.J. 2017. Gel-forming mucins form distinct morphologic structures in airways. Proc. Natl. Acad. Sc.i USA. V. 114. P. 6842. https://doi.org/10.1073/pnas.1703228114Owen D.H., Giffin M.J., Baylis J.M., Smith M.D., Carbone D.P., On K. 2019. DLL3: a new target in small cell lung cancer. J. Hematol. Oncol. V. 12. P. 61. https://doi.org/10.1186/s13045-019-0745-2Pancevich-Wojtkiewicz J. 2016. Epidermal growth factor receptor and notch signaling in non-small cell lung cancer. Cancer Med. V. 5. P. 3572. https://doi.org/10.1002/cam4.944Qin X., Zhang Z., Xu H., Wu Y. 2011. Notch signaling protects retina from nuclear factor-κB- and poly-ADP-ribose-polymerase-mediated apoptosis under high-glucose stimulation. Acta Biochim. Biophys. Sin. (Shanghai). V. 43. P. 703. https://doi.org/10.1093/abbs/gmr069Sharif A., Shaji A., Chammaa M., Pawlik E., Fernandez-Valdivia R. Sharif A. et al. 2020. Notch Transduction in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. V. 21. P. 5691. https://doi.org/10.3390/ijms21165691Sinha K., Das J., Pal P.B., Sil P.S. 2013. Oxidative stress: mitochondrial-dependent and mitochondrial-independent pathways of apoptosis. Arch. Toxicol. V. 87. P. 1157. https://doi.org/10.1007/s00204-013-1034-4Small R. J., Bacmeister J., Bailey D., Baker A., Bishop S., Bryan F., Caron J., Dennis J., Gent P., Hsu H.M., Jochum M., Lawrence D., Muñoz E., diNezio P., Scheitlin T. et al. 2014. A new synoptic scale resolving global climate simulation using the community earth system model. J. Adv. Model. Earth Syst. V. 6. P. 1065. https://doi.org/10.1002/2014MS000363Sosa Iglesias V., Juranno L., Dubois L.J., Theis J., Voice M. 2018. Drug resistance in non-small cell lung cancer: potential for targeting NOTCH? Front. Oncol. V. 8. P. 267. https://doi.org/10.3389/fonc.2018.00267Sparaneo A., Fabrizio F.P., Muscarella L.A. 2016. Transmission of Nrf2 and Notch signals in lung cancer: near the intersection. Oxid. Med. Cell. Longev. V. 2016. P. 7316492. https://doi.org/10.1155/2016/7316492Tindemans I., van Schoonhoven A., KleinJan A., de Bruijn M.J., Lukkes M., van Nimwegen M., van den Branden A., Bergen I.M., Corneth O.B., van IJcken W.F., Stadhouders R., Hendriks R.W. 2020. Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress. J. Clin. Invest. V. 130. P. 3576. https://doi.org/10.1172/JCI128310Tsao P., Wei S., Wu M., Huang M., Lin H., Lee M. 2011. Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development. Development. V. 138. P. 3533. https://doi.org/10.1242/dev.063727Wang Y., Xu J., Meng Y., Adcock I.M., Yao X. 2018. Role of inflammatory cells in airway remodeling in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. V. 13. P. 3341. https://doi.org/10.2147/COPD.S176122Whitsett J.A. 2018. Airway Epithelial Differentiation and Mucociliary Clearance. Ann. Am. Thorac. Soc. V. 15. P. S143. https://doi.org/10.1513/AnnalsATS.201802-128AWYu L., Li J. 2022. Punicalagin Alleviates Aged Bronchial Asthma by Inhibiting Th2 Differentiation through IL-4/STAT6 and Jagged1/Notch Pathways. J. Healthc. Eng. V. 2022. P. 1184677. https://doi.org/10.1155/2022/1184677Zeng Z., Wang L., Ma W., Zheng R., Zhang H., Zeng X., Zhang H., Zhang W. 2019. Inhibiting the Notch signaling pathway suppresses Th17-associated airway hyperresponsiveness in obese asthmatic mice. Lab. Invest. V. 99. P. 1784. https://doi.org/10.1038/s41374-019-0294-xZhou B., Lin W., Long Y., Yang Y., Zhang H., Wu K., Chu Q. 2022. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct. Target. Ther. V. 7. P. 95. https://doi.org/10.1038/s41392-022-00934-yZong D., Ouyang R., Li J., Chen Y., Chen P. 2016. Notch signaling in lung diseases: focus on Notch1 and Notch3. Ther. Adv. Respir. Dis. V. 10. P. 468. https://doi.org/10.1177/1753465816654873