Связь метаболической дисрегуляции с нейроиммунным воспалением дыхательных путей при бронхиальной астме

   В научной литературе последних лет активно обсуждаются нейроиммунные механизмы и их роль в патогенезе бронхиальной астмы (БА). Появляются данные о взаимосвязи нейротрофических факторов с липидным метаболизмом при астме. При всей значимости существующих исследований, данных литературы недостаточно для обоснования нейро-иммуно-липидной модели БА, определяющей патогенетическую взаимосвязь между тремя системами. Нейротрофический фактор мозга (BDNF – brain-derived neurotrophic factor) вовлекается в патогенез гиперреактивности и ремоделирования бронхов, объединяя нейроиммунные механизмы патогенеза БА. Нарушения липидного метаболизма при БА, включая дисбаланс провоспалительных и противовоспалительных липидных медиаторов, а также изменения уровня сфинголипидов и холестерина клеточных мембран, способны влиять на экспрессию BDNF и его рецептора, формирующих BDNF/TrkB сигнальный путь. Это позволяет рассматривать взаимоотношения липидов и нейротрофинов как механизм, связывающий метаболическую дисрегуляцию с нейроиммунным воспалением и ремоделированием дыхательных путей при БА. В данном механизме липидам отводится роль медиаторов, модулирующих активность BDNF за счет активации сигнальных путей, регулирующих транскрипцию гена BDNF. Дальнейшие исследования позволят обосновать единую нейро-иммунолипидную модель патогенеза БА.

1. Grunwell J.R., Fitzpatrick A.M. Asthma phenotypes and biomarkers // Respir. Care. 2025. Vol. 70, № 6. P. 649–674. doi: 10.1089/respcare.12352

2. Sahnoon L., Bajbouj K., Mahboub B., Hamoudi R., Hamid Q. Targeting IL-13 and IL-4 in asthma: therapeutic implications on airway remodeling in severe asthma // Clin. Rev. Allergy Immunol. 2025. Vol. 68, № 1. Article number: 44. doi: 10.1007/s12016-025-09045-2

3. Sabu Kattuman E.E., Teegala L.R., Darzi S., Thodeti C.K., Paruchuri S. Leukotrienes: bridging the inflammatory gap in asthma and inflammatory bowel diseases (IBD) // Compr. Physiol. 2025. Vol. 15, № 3. Article number: 70022. doi: 10.1002/cph4.70022

4. Ye Q., Barrett N., Balestrieri B. Bioactive lipids: accessible indicators toward improved diagnosis and treatment of asthma // J. Allergy Clin. Immunol. 2022. Vol. 150, № 4. P. 790–792. doi: 10.1016/j.jaci.2022.08.013

5. Pavón-Romero G.F., Serrano-Pérez N.H., García-Sánchez L., Ramírez-Jiménez F., Terán L.M. Neuroimmune pathophysiology in asthma // Front. Cell Dev. Biol. 2021. Vol. 9. Article number: 663535. doi: 10.3389/fcell.2021.663535

6. Vafaee F., Shirzad S., Shamsi F., Boskabady M.H. Neuroscience and treatment of asthma, new therapeutic strategies and future aspects // Life Sci. 2022. Vol. 292. Article number: 120175. doi: 10.1016/j.lfs.2021.120175

7. Chen Q., Jia N., Liu J., Xu C., Shi S., Wang F., Wang Z. Neuroimmune circuits in respiratory pathophysiology: decoding molecular crosstalk for precision therapeutic targeting // Ann. Med. 2026. Vol. 58, № 1. Article number: 2620337. doi: 10.1080/07853890.2026.2620337

8. Watanabe T., Fajt M.L., Trudeau J.B., Voraphani N., Hu H., Zhou X., Holguin F., Wenzel S.E. Brain-derived neurotrophic factor expression in asthma. Association with severity and type 2 inflammatory processes // Am. J. Respir. Cell Mol. Biol. 2015. Vol. 53, № 6. P. 844–852. doi: 10.1165/rcmb.2015-0015OC

9. Roos B.B., Teske J., Bhallamudi S., Pabelick C.M., Sathish V., Prakash Y.S. Neurotrophin regulation and signaling in airway smooth muscle // Adv. Exp. Med. Biol. 2021. Vol. 1304. P. 109–121. doi: 10.1007/978-3-030-68748-9_7

10. Jing S., Li X., Liu W., Li X. Brain-derived neurotrophic factor inhibits the wound-healing and cell proliferative ability of human airway epithelial cells in asthmatic children // Med. Sci. Monit. 2020. Vol. 26. Article number: 923680. doi: 10.12659/MSM.923680

11. Prakash Y.S., Martin R.J. Brain-derived neurotrophic factor in the airways // Pharmacol. Ther. 2014. Vol. 143, № 1. P. 74–86. doi: 10.1016/j.pharmthera.2014.02.006

12. Crosson T., Bhat S., Wang J.C., Salaun C., Fontaine E., Roversi K., Herzog H., Rafei M., Blunck R., Talbot S. Cytokines reprogram airway sensory neurons in asthma // Cell Rep. 2024. Vol. 43, № 12. Article number: 115045. doi: 10.1016/j.celrep.2024.115045

13. Braun A., Lommatzsch M., Neuhaus-Steinmetz U., Quarcoo D., Glaab T., McGregor G.P., Fischer A., Renz H. Brain-derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation // Br. J. Pharmacol. 2004. Vol. 141, № 3. P. 431–440. doi: 10.1038/sj.bjp.0705638

14. Hutchinson A.J., Chou C.-L., Israel D.D., Xu W., Regan J.W. Activation of EP2 prostanoid receptors in human glial cell lines stimulates the secretion of BDNF // Neurochem. Int. 2009. Vol. 54, № 7. P. 439–446. doi: 10.1016/j.neuint.2009.01.018

15. Yu Y., Jiang J. COX-2/PGE2 axis regulates hippocampal BDNF/TrkB signaling via EP2 receptor after prolonged seizures // Epilepsia Open 2020. Vol. 5, № 3. P. 418–431. doi: 10.1002/epi4.12409

16. Haider K., Al Mulla Hummadi Y.M.K., Muhamad Guaim R., Ahmeid M. Montelukast altered BDNF and CHRNA7 gene expression were associated with behavioral changes in rats // F1000Res. 2025. Vol. 14. Article number: 963. doi: 10.12688/f1000research.169688.1

17. Hsi L.C., Wilson L.C., Eling T.E. Opposing effects of 13-hydroxyoctadecadienoic acid on MAPK signalling pathways // J. Biol. Chem. 2002. Vol. 277, № 43. P. 40558–40564. doi: 10.1074/jbc.M203522200.

18. Wickstead E.S., Elliott B.T., Pokorny S., Biggs C., Getting S.J., McArthur S. Stimulation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activity by suppressing NFkB activity // Int. J. Mol. Sci. 2023. Vol. 24, № 21. Article number: 15996. doi: 10.3390/ijms242115996

19. Johnson R.K., Manke J., Campbell M., Armstrong M., Boorgula M.P., Pinheiro G., Santana C.V.N., Mathias R.A., Barnes K.C., Cruz A. Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects // J. Allergy Clin. Immunol. 2022. Vol. 150, № 4. P. 965–971.e8. doi: 10.1016/j.jaci.2022.02.026

20. Miyata J., Fukunaga K., Iwamoto R., Isobe Y., Niimi K., Takamiya R., Takihara T., Tomomatsu K., Suzuki Y., Oguma T. Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma // J. Allergy Clin. Immunol. 2013. Vol. 131, № 2. P. 353–360.e2. doi: т10.1016/j.jaci.2012.07.048

21. Suzuki S., Numakawa T., Shimazu K., Koshimizu H., Hara T., Hatanaka H., Mei L., Lu B. BDNF-induced recruitment of TrkB receptor into lipid rafts: roles in synaptic modulation // J. Cell. Biol. 2004 Vol. 167, № 6. P. 1205–1215. doi: 10.1083/jcb.200404106

22. Cannarozzo C., Fred S.M., Girych M., Biojone C., Enkavi G., Róg T., Vattulainen I., Casarotto P.C., Castrén E. Cholesterol-recognition motifs in the transmembrane domain of the tyrosine kinase receptor family: the case of TRKB // Eur. J. Neurosci. 2021. Vol. 53, № 10. P. 3311–3322. doi: 10.1111/ejn.15218

23. Munsch T., Meis S., Lessmann V. Cholesterol depletion inhibits BDNF-dependent spike timing-dependent plasticity at thalamo-amygdala synapses // Front. Cell. Neurosci. 2026. Vol. 20. Article number: 1769264. doi: 10.3389/fncel.2026.1769264

24. Viljetić B., Vukojević V., Ninković M. Lipid rafts: the maestros of cellular signalling // Biomolecules. 2024. Vol. 14, № 3. Article number: 362. doi: 10.3390/biom14030362

25. Quinville B.M., Deschenes N.M., Ryckman A.E., Walia J.S. A comprehensive review: sphingolipid metabolism and implications of disruption in sphingolipid homeostasis // Int. J. Mol. Sci. 2021. Vol. 22, № 11. Article number: 5793. doi: 10.3390/ijms22115793

26. Luthers C.R., Dunn T.M., Snow A.L. ORMDL3 and asthma: linking sphingolipid regulation to altered T cell function // Front. Immunol. 2020. Vol. 11. Article number: 597945. doi: 10.3389/fimmu.2020.597945

27. Maguire T.J., Yung S., Ortiz-Zapater E., Kayode O.S., Till S., Corrigan C., Siew L.Q.C., Knock G.A., Woszczek G. Sphingo-sine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation // J. Allergy Clin. Immunol. 2023. Vol. 152, № 5. P. 1131–1140.e6. doi: 10.1016/j.jaci.2023.05.028

28. Yoshida K. Abnormal saturated fatty acids and sphingolipid metabolism in asthma // Respir. Investig. 2024. Vol. 62, № 4. P. 526–530. doi: 10.1016/j.resinv.2024.04.006

29. Listyoko A.S., Okazaki R., Harada T., Inui G., Yamasaki A. Impact of obesity on airway remodeling in asthma: pathophysiological insights and clinical implications // Front. Allergy. 2024. Vol. 5. Article number: 1365801. doi: 10.3389/falgy.2024.1365801

30. Godinho-Silva C., Rendas M., Veiga-Fernandes H. Neuro-ILC interactions in host physiology and defence // Eur. J. Immunol. 2025. Vol. 55, № 8. Article number: 70037. doi: 10.1002/eji.70037

31. Warner W.S., Rose M., Yeoh S., Muhlestein W.E., Noroozi Gilandehi S., Mahan M.A. The neuroimmune microenvironment of peripheral nerve injury: mechanisms, pathophysiology, and therapeutic implications // Front. Surg. 2026. Vol. 13. Article number: 1745990. doi: 10.3389/fsurg.2026.1745990

32. Mueller K.L., Hines P.J., Travis J. Neuroimmunology // Science. 2016. Vol. 353, № 6301. P. 760–761. doi: 10.1126/science.353.6301.760

33. Chen J., Lai X., Song Y. Neuroimmune recognition and regulation in the respiratory system // Eur. Respir. Rev. 2024. Vol. 33, № 172. Article number: 240008. doi: 10.1183/16000617.0008-2024

34. Shouman K., Benarroch E.E. Peripheral neuroimmune interactions : selected review and some clinical implications // Clin. Auton. Res. 2021. Vol. 31, № 4. P. 477–489. doi: 10.1007/s10286-021-00787-5

35. Kabata H., Artis D. Neuro-immune crosstalk and allergic inflammation // J. Clin. Invest. 2019. Vol. 129, № 4. P. 1475–1482. doi: 10.1172/JCI124609

36. Nockher W.A., Renz H. Neurotrophins and asthma: novel insight into neuroimmune interaction // J. Allergy Clin. Immunol. 2006. Vol. 117, № 1. P. 67–71. doi: 10.1016/j.jaci.2005.08.029

37. Mirzahosseini G., Adam J.M., Nasoohi S., El-Remessy A.B., Ishrat T. Lost in translation: neurotrophins biology and function in the neurovascular unit // Neuroscientist. 2023. Vol. 29, № 6. P. 694–714. doi: 10.1177/10738584221104982

38. Li Q., Hu Y.Z., Gao S., Wang P.F., Hu Z.L., Dai R.P. ProBDNF and its receptors in immune-mediated inflammatory diseases: novel insights into the regulation of metabolism and mitochondria // Front. Immunol. 2023. Vol. 14. Article number: 1155333. doi: 10.3389/fimmu.2023.1155333

39. Freeman M.R., Sathish V., Manlove L., Wang S., Britt R.D. Jr., Thompson M.A., Pabelick C.M., Prakash Y.S. Brain-derived neurotrophic factor and airway fibrosis in asthma // Am. J. Physiol. Lung Cell Mol. Physiol. 2017. Vol. 313, № 2. P. L360–L370. doi: 10.1152/ajplung.00580.2016

40. Sreter K.B., Popovic-Grle S., Lampalo M., Konjevod M., Tudor L., Nikolac Perkovic M., Jukic I., Bingulac-Popovic J., Safic Stanic H., Markeljevic J., Pivac N., Svob Strac D. Plasma brain-derived neurotrophic factor (BDNF) concentration and BDNF/TrkB gene polymorphisms in croatian adults with asthma // J. Pers. Med. 2020. Vol. 10, № 4. Article number: 189. doi: 10.3390/jpm10040189

41. Wang M., Xie Y., Qin D. Proteolytic cleavage of proBDNF to mBDNF in neuropsychiatric and neurodegenerative diseases // Brain Res. Bull. 2021. Vol. 166. P. 172–184. doi: 10.1016/j.brainresbull.2020.11.005

42. Shen W.Y., Luo C., Hurtado P.R., Liu X.J., Luo R.Y., Li H. Up-regulation of proBDNF/p75(NTR) signaling in antibody-secreting cells drives systemic lupus erythematosus // Sci. Adv. 2022. Vol. 8, № 3. Article number: eabj2797. doi: 10.1126/sciadv.abj2797

43. Eggert S., Kins S., Endres K., Brigadski T. Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer's disease // Biol. Chem. 2022. Vol. 403, № 1. P. 43–71. doi: 10.1515/hsz-2021-0330

44. Kanato Y., Ono S., Kitajima K., Sato C. Complex formation of a brain-derived neurotrophic factor and glycosaminoglycans // Biosci. Biotechnol. Biochem. 2009. Vol. 73, № 12. P. 2735–2741. doi: 10.1271/bbb.90637

45. Wang Y., Liang J., Xu B., Yang J., Wu Z., Cheng L. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury // Life Sci. 2024. Vol. 336. Article number: 122282. doi: 10.1016/j.lfs.2023.122282

46. Zhao Y., Li X., Xu Z., Hao L., Zhang Y., Liu Z. PI3K-AKT-mTOR signaling pathway: the intersection of allergic asthma // Pharmazie. 2019. Vol. 74, № 10. P. 598–600. doi: 10.1691/ph.2019.9080

47. Saleem S. Targeting MAPK signaling: a promising approach for treating inflammatory lung disease // Pathol. Res. Pract. 2024. Vol. 254. Article number: 155122. doi: 10.1016/j.prp.2024.155122

48. Zarneshan S.N., Fakhri S., Khan H. Targeting Akt/CREB/BDNF signaling pathway by ginsenosides in neurodegenerative diseases: a mechanistic approach // Pharmacol. Res. 2022. Vol. 177. Article number: 106099. doi: 10.1016/j.phrs.2022.106099

49. Raslan A.A., Abdel Baky N.A., Shehata A.M., El-Latif H.A.A. Modulation of CREB and its associated upstream signaling pathways in pesticide-induced neurotoxicity // Mol. Cell. Biochem. 2022. Vol. 477, № 1. P. 2621–2642. doi: 10.1007/s11010-022-04472-7

50. Chen R., Chen W., Li P., Zhao Y., Zeng Q., Chen W., Cao D. Function and application of brain-derived neurotrophic factor pre-cursors (review) // Int. J. Mol. Med. 2025. Vol. 56, № 1. Article number: 105. doi: 10.3892/ijmm.2025.5546

51. Abd-Elaziz K., Jesenak M., Vasakova M., Diamant Z. Revisiting matrix metalloproteinase 12: its role in pathophysiology of asthma and related pulmonary diseases // Curr. Opin. Pulm. Med. 2021. Vol. 27, № 1. P. 54–60. doi: 10.1097/MCP.0000000000000743

52. Tholozan F.M.D., Gribbon C., Li Z., Goldberg M.W., Prescott A.R., McKie N. FGF-2 release from the lens capsule by MMP-2 maintains lens epithelial cell viability // Mol. Biol. Cell. 2007. Vol. 18, № 11. P. 4222–4231. doi: 10.1091/mbc.E06-05-0416

53. Kim J., Kim R.J., Lee S.B., Suh M.C. Protein-protein interactions in fatty acid elongase complexes are important for very-long-chain fatty acid synthesis // J. Exp. Bot. 2022. Vol. 73, № 9. P. 3004–3017. doi: 10.1093/jxb/erab543

54. Kytikova O., Denisenko Y., Novgorodtseva T., Kovalenko I., Antonyuk M. Polyunsaturated fatty acids and lipid mediators controlling chronic inflammation in asthma // Russ. Open Med. J. 2023. Vol. 1, № 12. Article number: 2. doi: 10.15275/rusomj.2023.0201

55. Biernacki M., Skrzydlewska E. Metabolic pathways of eicosanoids-derivatives of arachidonic acid and their significance in skin // Cell. Mol. Biol. Lett. 2025. Vol. 30. Article number: 7. doi: 10.1186/s11658-025-00685-y

56. Picado C., Machado-Carvalho L., Roca-Ferrer J. Low prostaglandin E2 but high prostaglandin D2, a paradoxical dissociation in arachidonic acid metabolism in aspirin-exacerbated airway disease: role of airway epithelium // J. Clin. Med. 2024. Vol. 13, № 23. Article number: 7416. doi: 10.3390/jcm13237416

57. Tassan Mazzocco M., Murtaj V., Martins D., Schellino R., Coliva A., Toninelli E., Vercelli A., Turkheimer F., Belloli S., Moresco R.M. Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity // J. Neuroinflammation. 2023. Vol. 20, № 1. Article number: 34. doi: 10.1186/s12974-023-02714-z

58. Zhang J., Li Z., Fan M., Jin W. Lipoxins in the nervous system: brighter prospects for neuroprotection // Front. Pharmacol. 2022. Vol. 13. Article number: 781889. doi: 10.3389/fphar.2022.781889

59. Mabalirajan U., Rehman R., Ahmad T., Kumar S., Singh S., Leishangthem G.D., Aich J., Kumar M., Khanna K., Singh V.P., Dinda A.K., Biswal S., Agrawal A., Ghosh B. Linoleic acid metabolite drives severe asthma by causing airway epithelial injury // Sci. Rep. 2013. Vol. 3. Article number: 1349. doi: 10.1038/srep01349

60. Serhan C.N. Novel pro-resolving lipid mediators in inflammation are leads for resolution physiology // Nature. 2014. Vol. 510, № 7503. P. 92–101. doi: 10.1038/nature13479

61. Yu C.X., Shi Z.A., Ou G.C., Chen X.J., Liu Q., Zeng D., Nie X.J., Chen J.J. Maresin-2 alleviates allergic airway inflammation in mice by inhibiting the activation of NLRP3 inflammasome, Th2 type immune response and oxidative stress // Mol. Immunol. 2022. Vol. 146. P. 78–86. doi: 10.1016/j.molimm.2022.03.118

62. Ou G., Liu Q., Yu C., Chen X., Zhang W., Chen Y., Wang T., Luo Y., Jiang G., Zhu M. The protective effects of maresin 1 in the OVA-induced asthma mouse model // Mediators Inflamm. 2021. Vol. 2021. Article number: 4131420. doi: 10.1155/2021/4131420

63. Antunes G.L., Silveira J.S., Luft C., Greggio S., Venturin G.T., Schmitz F., Biasibetti-Brendler H., Vuolo F., Dal-Pizzol F., da Costa J.C., Wyse A.T.S., Pitrez P.M., da Cunha A.A. Airway inflammation induces anxiety-like behavior through neuroinflammatory, neurochemical, and neurometabolic changes in an allergic asthma model // Metab. Brain Dis. 2022. Vol. 37, № 4. P. 911–926. doi: 10.1007/s11011-022-00907-8

64. Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W. Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction // Neurobiol. Aging. 2008. Vol. 29, № 9. P. 1380–1393. doi: 10.1016/j.neurobiolaging.2007.02.027

65. Ortega Á., Duran P., Garrido B., Manzano A., Navarro C., Silva A., Rojas M., De Sanctis J.B., Radzioch D., Rivera-Porras D., Paredes C.S., Bermúdez V. Specialized pro-resolving lipid mediators in pulmonary diseases: molecular and therapeutic implications // Molecules. 2025. Vol. 30, № 10. Article number: 2212. doi: 10.3390/molecules30102212

66. Krishnamoorthy N., Burkett P.R., Dalli J., Abdulnour R.-E.E., Colas R., Ramon S., Phipps R.P., Petasis N.A., Kuchroo V.K., Serhan C.N. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation // J. Immunol. 2015. Vol. 194, № 3. P. 863–867. doi: 10.4049/jimmunol.1402534

67. Mukherjee P.K., Marcheselli V.L., Barreiro S., Hu J., Bok D., Bazan N.G. Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling // Proc. Natl. Acad. Sci. U.S.A. 2007. Vol. 104, № 32. P. 13152–13157. doi: 10.1073/pnas.0705949104

68. Assaife-Lopes N., Sousa V.C., Pereira D.B., Ribeiro J.A., Sebastião A.M. Regulation of TrkB receptor translocation to lipid rafts by adenosine A(2A) receptors and its functional implications for BDNF-induced regulation of synaptic plasticity // Purinergic. Signal. 2014. Vol. 10, № 2. P. 251–267. doi: 10.1007/s11302-013-9383-2. Erratum in: Purinergic. Signal. 2024; Vol. 20, № 3. Article numner: 313. doi: 10.1007/s11302-024-10011-4

69. Chen Y., Checa A., Zhang P., Huang M., Kelly R.S., Kim M. Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors // Allergy. 2024. Vol. 79, № 2. P. 404–418. doi: 10.1111/all.15942

70. Heras A.F., Brown S., Worgall T.S., Perez-Zoghbi J.F., Worgall S. Sphingosine-1-phosphate – sphinganine-1-phosphate imbalance drives airway hyperreactivity // medRxiv. 2026. Article number: 2026.03.15.26348448. doi: 10.64898/2026.03.15.26348448

71. Ha A.W., Garcia J.G.N., Dudek S.M. S1PR2 signaling in the lung: understanding its role in health and disease // Cells. 2026. Vol. 15, № 1. Article number: 10. doi: 10.3390/cells15010010

72. Yang J., Zhong W., Li Q., Zhang W., Lin W., Fan X., He Y., Ma N. Sphingosine-1-phosphate signaling in respiratory diseases: mechanisms and therapeutic perspectives // Int. Immunopharmacol. 2025. Vol. 166. Article number: 115578. doi: 10.1016/j.intimp.2025.115578