Роль нейровоспаления в патогенезе отека головного мозга и геморрагической трансформации при ишемическом инсульте: механизмы и терапевтические мишени.

Острое нарушение мозгового кровообращения является одной из ведущих причин инвалидизации и смертности во всем мире. Учитывая значительное увеличение продолжительности жизни населения, инсульт в ближайшие несколько десятилетий будет оставаться серьезной медико-социальной проблемой. Среди различных причин инсульта преобладает ишемическое повреждение головного мозга. В основе ишемического инсульта лежит снижение интенсивности кровоснабжения тканей головного мозга, в результате которого уменьшается доставка к нейронам необходимого количества глюкозы и кислорода, которые требуются для обеспечения нормальной функции этого органа. В то же время во многих случаях спонтанное либо медикаментозное восстановление кровотока после периода ишемии сопровождается парадоксальным нарастанием повреждения, в связи с чем процесс повреждения ткани головного мозга при нарушениях кровообращения целесообразно рассматривать в контексте ишемического-реперфузионного повреждения (ИРП). Одним из ключевых механизмов ИРП головного мозга является воспалительная реакция. В процессе вторичного иммунного повреждения головного мозга принимают участие как механизмы врожденного иммунитета, проявляющиеся лейкоцитарной инфильтрацией поврежденного участка головного мозга, так и антиген-зависимые реакции адаптивного иммунитета. Одним из важнейших проявлений нейровоспаления при ИРП головного мозга является повышение транси парацеллюлярной проницаемости гематоэнцефалического барьера, которое лежит в основе развития вазогенного отека головного мозга и геморрагической трансформации очага. В настоящем обзоре рассмотрены современные представления о молекулярных механизмах, связывающих асептическое воспаление, отек и геморрагическую трансформацию.

1. Garcia JH, Liu KF, Yoshida Y, et al. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994; 144(1):188–199.

2. Mena H, Cadavid D, Rushing EJ. Human cerebral infarct: a proposed histopathologic classification based on 137 cases. Acta Neuropathol. 2004; 108(6):524–530.

3. Iadecola C, Buckwalter MS, Anrather J. Immune responses to stroke: mechanisms, modulation, and therapeutic potential. J Clin Invest. 2020; 130(6):2777– 2788.

4. Nakamura K, Shichita T. Cellular and molecular mechanisms of sterile inflammation in ischaemic stroke. J Biochem. 2019; 165(6):459–464.

5. Koyama R, Shichita T. Glial roles in sterile inflammation after ischemic stroke. Neurosci Res. 2023; 187:67–71.

6. Zhao D, Zeng Z, Mo H, et al. Orexin-A inhibits cerebral ischaemic inflammatory injury mediated by the nuclear factor-κB signalling pathway and alleviates strokeinduced immunodepression in mice. Brain Res Bull. 2021; 174:296–304.

7. Puleo MG, Miceli S, Di Chiara T, et al. Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis. Pharmaceuticals (Basel). 2022; 15(10):1168.

8. Gao L, Dong Q, Song Z, et al. NLRP3 inflammasome: a promising target in ischemic stroke. Inflamm Res. 2017; 66(1):17–24.

9. Gronberg NV, Johansen FF, Kristiansen U, et al. Leukocyte infiltration in experimental stroke. J Neuroinflammation. 2013; 10:115.

10. Herz J, Sabellek P, Lane TE, et al. Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice. Stroke. 2015; 46(10):2916–2925.

11. Wang C, Börger V, Sardari M, et al. Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils. Stroke. 2020; 51(6):1825– 1834.

12. El Amki M, Glück C, Binder N, et al. Neutrophils obstructing brain capillaries are a major cause of no-reflow in ischemic stroke. Cell Rep. 2020; 33(2):108260.

13. De Meyer SF, Langhauser F, Haupeltshofer S, et al. Thromboinflammation in brain ischemia: recent updates and future perspectives. Stroke. 2022; 53(5):1487–1499.

14. Elkind MSV, Veltkamp R, Montaner J, et al. Natalizumab in acute ischemic stroke (ACTION II): a randomized, placebo-controlled trial. Neurology. 2020; 95(8):e1091–e1104.

15. Mohamud Yusuf A, Hagemann N, Ludewig P, et al. Roles of polymorphonuclear neutrophils in ischemic brain injury and post-ischemic brain remodeling. Front Immunol. 2022; 12:825572.

16. García-Culebras A, Durán-Laforet V, PeñaMartínez C, et al. Role of TLR4 (Toll-Like Receptor 4) in N1/N2 neutrophil programming after stroke. Stroke. 2019; 50(10):2922–2932.

17. Garcia-Bonilla L, Faraco G, Moore J, et al. Spatio-temporal profile, phenotypic diversity, and fate of recruited monocytes into the post-ischemic brain. J Neuroinflammation. 2016; 13(1):285.

18. Hurn PD, Subramanian S, Parker SM, et al. Tand B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007; 27(11):1798–1805.

19. Kleinschnitz C, Schwab N, Kraft P, et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood. 2010; 115(18):3835–3842.

20. Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009; 15(2):192–199.

21. Knowland D, Arac A, Sekiguchi KJ, et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron. 2014; 82(3):603–617.

22. Yang C, Hawkins KE, Doré S, et al. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019; 316(2):C135–C153.

23. Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 2011; 42(11):3323–3328.

24. Allen C, Thornton P, Denes A, et al. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA. J Immunol. 2012; 189(1):381–392.

25. Herisson F, Frodermann V, Courties G, et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci. 2018; 21(9):1209–1217.

26. Engelhardt B, Wolburg-Buchholz K, Wolburg H. Involvement of the choroid plexus in central nervous system inflammation. Microsc Res Tech. 2001; 52(1):112–129.

27. Széplaki G, Szegedi R, Hirschberg K, et al. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes. Atherosclerosis. 2009; 204(1):315–320.

28. Orsini F, Fumagalli S, Császár E, et al. MannoseBinding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α. Arterioscler Thromb Vasc Biol. 2018; 38(11):2678–2690.

29. Osthoff M, Katan M, Fluri F, et al. Mannosebinding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. PLoS One. 2011; 6(6):e21338.

30. Bower NI, Hogan BM. Brain drains: new insights into brain clearance pathways from lymphatic biology. J Mol Med (Berl). 2018; 96(5):383–390.

31. Chapman KZ, Dale VQ, Dénes A, et al. A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. J Cereb Blood Flow Metab. 2009; 29(11):1764–1768.

32. Langhorne P, Stott DJ, Robertson L, et al. Medical complications after stroke: a multicenter study. Stroke. 2000; 31(6):1223–1229.

33. Prass K, Meisel C, Höflich C, et al. Strokeinduced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003; 198(5):725–736.

34. Singh V, Roth S, Llovera G, et al. Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke. J Neurosci. 2016; 36(28):7428–7440.

35. Ortega SB, Noorbhai I, Poinsatte K, et al. Stroke induces a rapid adaptive autoimmune response to novel neuronal antigens. Discov Med. 2015; 19(106):381–392.

36. Youngchaiyud U, Coates AS, Whittingham S, et al. Cellular-immune response to myelin protein: absence in multiple sclerosis and presence in cerebrovascular accidents. Aust N Z J Med. 1974; 4(6):535–538.

37. Prüss H, Iggena D, Baldinger T, et al. Evidence of intrathecal immunoglobulin synthesis in stroke: a cohort study. Arch Neurol. 2012; 69(6):714–717.

38. Kliper E, Bashat DB, Bornstein NM, et al. Cognitive decline after stroke: relation to inflammatory biomarkers and hippocampal volume. Stroke. 2013; 44(5):1433–1435.

39. Nawabi J, Flottmann F, Hanning U, et al. Futile Recanalization With Poor Clinical Outcome Is Associated With Increased Edema Volume After Ischemic Stroke. Invest Radiol. 2019; 54(5):282–287.

40. McKeown ME, Prasad A, Kobsa J, et al. Midline Shift Greater than 3 mm Independently Predicts Outcome After Ischemic Stroke. Neurocrit Care. 2022; 36(1):46–51.

41. Задворнов А.А., Голомидов А.В., Григорьев Е.В. Клиническая патофизиология отека головного мозга (часть 2). Вестник анестезиологии и реаниматологии. 2017; 14(4):52–60.

42. Gu Y, Zhou C, Piao Z, et al. Cerebral edema after ischemic stroke: Pathophysiology and underlying mechanisms. Front Neurosci. 2022; 16:988283.

43. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016; 36(3):513–538.

44. MacAulay N. Molecular mechanisms of brain water transport. Nat Rev Neurosci. 2021; 22(6):326–344.

45. Kitchen P, Salman MM, Halsey AM, et al. Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema. Cell. 2020; 181(4):784–799.e19.

46. Zeuthen T, Meinild AK, Klaerke DA, et al. Water transport by the Na+/glucose cotransporter under isotonic conditions. Biol Cell. 1997; 89(5-6):307–312.

47. MacAulay N, Zeuthen T. Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience. 2010; 168(4):941–956.

48. Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. 2003; 23(24):8568–8577.

49. Simard JM, Yurovsky V, Tsymbalyuk N, et al. Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke. 2009; 40(2):604–609.

50. Hamann S, Herrera-Perez JJ, Zeuthen T, et al. Cotransport of water by the Na+-K+-2Cl(-) cotransporter NKCC1 in mammalian epithelial cells. J Physiol. 2010; 588:4089–4101.

51. Zeuthen T. Cotransport of K+, Cland H2O by membrane proteins from choroid plexus epithelium of Necturus maculosus. J Physiol. 1994; 478:203–219.

52. Chen S, Shao L, Ma L. Cerebral Edema Formation After Stroke: Emphasis on Blood-Brain Barrier and the Lymphatic Drainage System of the Brain. Front Cell Neurosci. 2021; 15:716825.

53. Zhang C, Jiang M, Wang WQ, et al. Selective mGluR1 Negative Allosteric Modulator Reduces BloodBrain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage. Transl Stroke Res. 2020; 11(4):799–811.

54. Moy AB, Van Engelenhoven J, Bodmer J, et al. Histamine and thrombin modulate endothelial focal adhesion through centripetal and centrifugal forces. J Clin Invest. 1996; 97(4):1020–1027.

55. Dore-Duffy P, Wang X, Mehedi A, et al. Differential expression of capillary VEGF isoforms following traumatic brain injury. Neurol Res. 2007; 29(4):395–403.

56. Zhang ZG, Zhang L, Jiang Q, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000; 106(7):829–838.

57. Winkler L, Blasig R, Breitkreuz-Korff O, et al. Tight junctions in the blood-brain barrier promote edema formation and infarct size in stroke Ambivalent effects of sealing proteins. J Cereb Blood Flow Metab. 2021; 41(1):132–145.

58. Xing L, Wang B, Li J, et al. A Fluorogenic ONOO--Triggered Carbon Monoxide Donor for Mitigating Brain Ischemic Damage. J Am Chem Soc. 2022; 144(5):2114–2119.

59. Wang W, Li M, Chen Q, et al. Hemorrhagic Transformation after Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke: Mechanisms, Models, and Biomarkers. Mol Neurobiol. 2015; 52(3):1572–1579.

60. Campos F, Qin T, Castillo J, et al. Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model. Stroke. 2013; 44(2):505–511.

61. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359(13):1317–1329.

62. Laszló JM, Hortobágyi T. Hemorrhagic transformation of ischemic stroke. Vasc Dis Therap. 2017. 2:1–25.

63. Hong JM, Kim DS, Kim M. Hemorrhagic Transformation After Ischemic Stroke: Mechanisms and Management. Front Neurol. 2021; 12:703258.

64. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002; 39(3):279–291.

65. Rosell A, Ortega-Aznar A, Alvarez-Sabín J, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006; 37(6):1399–1406.

66. Suofu Y, Clark JF, Broderick JP, et al. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012; 212:180– 189.

67. Switzer JA, Hess DC, Ergul A, et al. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011; 42(9):2633–2635.

68. Wang X, Lee SR, Arai K, et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med. 2003; 9(10):1313– 1317.

69. Tsirka SE, Rogove AD, Bugge TH, et al. An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J Neurosci. 1997; 17(2):543–552.

70. Krizanac-Bengez L, Hossain M, Fazio V, et al. Loss of flow induces leukocyte-mediated MMP/TIMP imbalance in dynamic in vitro blood-brain barrier model: role of pro-inflammatory cytokines. Am J Physiol Cell Physiol. 2006; 291(4):C740–C749.

71. Dimitrijevic OB, Stamatovic SM, Keep RF, et al. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke. 2007; 38(4):1345–1353.