Evento Vascular Cerebral Isquémico: Respuesta Inflamatoria local, sistémica y su fenómeno de inmunosupresión post-evento.
Palabras clave:
Isquemia cerebral, marcadores inmunológicos, neuroinflamación, inmunoregulación.
Resumen
El evento vascular cerebral isquémico representa en la actualidad un problema de salud pública en México y en el mundo, con tasas elevadas de morbilidad y mortalidad principalmente en mayores de 60 años. Actualmente, se conoce que el sistema inmunológico juega un papel fundamental en la patogénesis del EVC en respuesta a isquemia de la unidad neurovascular, desencadenando una respuesta celular que genera un estado pro-inflamatorio que a su vez, promueve la reparación y regeneración neuronal. Sin embargo, por mecanismos que aún no han sido bien esclarecidos, se genera un estado de inmunosupresión posterior al evento isquémico conocido como fenómeno de inmunosupresión inducido por EVC. Otros mecanismos de la respuesta inflamatoria como el papel antagónico de diversas células y moléculas inflamatorias aún no han sido claramente establecidos. La única terapia actualmente aprobada en el periodo agudo post-isquémico es la terapia trombolítica con rtPa, sin embargo, únicamente otorga resultados benéficos en la minoría de los pacientes debido a la estrecha ventana terapéutica, debido a esto resulta imperante conocer la fisiopatología del evento y ampliar el estudio del componente inflamatorio para el desarrollo de terapias inmunológicas futuras. Esta revisión tiene como objetivo describir la respuesta inmunológica del EVC, sus principales biomarcadores periféricos, el fenómeno de inmunosupresión inducido por isquemia cerebral así como la terapia actual y las nuevas estrategias en el tratamiento de la neuroinflamación del EVC isquémico.
Citas
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[33] D, Doll, ˝Cytokines: The role in stroke and potential biomarkers and therapeutic targets“, Aging and Disease, vol. 5, no. 5, pp. 294-306, 2014.
[34] G. Jickling, ˝Blood biomarkers of ischemic stroke˝, Neurotherapeutics, vol. 8, pp. 349–360, 2011.
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[39] A. Chamorro, “Infection After Acute Ischemic Stroke. A Manifestation of Brain-Induced Immunodepression”, Stroke, vol. 38, pp. 1097-1103, 2007.
[40] S. Aslanyan, “Pneumonia and urinary tract infection after acute ischaemic stroke: a tertiary analysis of the GAIN international trial”, Eur. Jour. of Neur., vol. 11, pp. 49-53, 2004.
[41] B. Ovbiagele, “Frequency and Determinants of Pneumonia and Urinary Tract Infection During Stroke Hospitalization”, J. Stroke. Cerebrovasc. Dis., vol. 15, pp. 209-213, 2006.
[42] C. Meisel, “Central nervous system injury-induced immune deficiency syndrome”, Nat. Rev. Neuros., vol. 6, pp. 775-86, 2005.
[43] X. Urra, “Harms and Benefits of Lymphocyte Subpopulations in Patients with Acute Stroke”, Neurosci. J,, vol. 158, pp. 1174-1183, 2009.
[44] P. Li, “Adoptive Regulatory T-Cell Therapy Protects Against Cerebral Ischemia”, Ann. Neurol., 2013.
[45] K. Becker, “Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome”, Stroke., vol. 42, pp. 2763-2769, 2011.
[46] U. Dirnagl, “Stroke-induced immunodepression. Experimental evidence and clinical relevance”, Stroke, vol. 38, pp. 770-773, 2007.
[47] B. Famakin, “The Immune Response to Acute Focal Cerebral ischemia and Associated Post-stroke Immunoderession: A Focused Review”, Aging. Dis., vol. 5, pp. 307-326, 2014.
[48] R. Shim, “Ischemia, Immunosuppression and Infection—Tackling the Predicaments of Post-Stroke Complications”, Int. J. Mol. Sci., vol. 17, 2016.
[49] K. Prass, "Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation", J. Exp. Med., vol. 1, pp. 752-83, 2003.
[50] A. Chamorro, “The Early Systemic Prophylaxis of Infection After Stroke Study. A Randomized Clinical Trial”, Stroke., vol. 36, pp. 1495-1500, 2005.
[51] H. Harms, “Preventive Antibacterial Therapy in Acute Ischemic Stroke: A Randomized Controlled Trial”, PLoS One., vol. 3, 2008.
[52] H. Harms, “Influence of Stroke Localization on Autonomic Activation, Immunodepression, and Post-Stroke Infection”, Cerebrovasc. Dis., vol. 32, pp. 552-560, 2011.
[53] W. Westendrop, “The Preventive Antibiotics in Stroke Study (PASS): a pragmatic radomised open-label masked endpoint clinical trial”, Lancet., 2015.
[54] T. Dziedzic, “Beta-blockers reduce the risk of early dead in ischemic stroke” J. Neurol. Sci., vol. 252, pp. 53-56, 2007.
[55] C.H. Wong, “Functional innervation of hepatic iNKT cells is immunosuppressive following stroke”, Science, vol. 334, pp. 101-105, 2011.
[56] S. Lenglet, “Recombinant tissue plasminogen activator enhaces microglial cell recruitment after stroke in mice”. jou of cbf and metabolism (2014) 34, 802-812
[57] E.C. Jauch, ˝Guidelines for the early management of patients with acute ischemic stroke˝, Stroke, vol. 44, pp. 870-947, 2013.
[58] C.J. Siao, ˝Cell-type specific roles for tissue plasminogen activator realeased by neurons or microglia after excitotoxic injury˝, J. Neurosci., vol. 23, pp. 3234-3242, 2003.
[59] A. Reijerkerek, ˝Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier˝, J. Immunol. vol. 181, pp. 3567-3574, 2008.
[60] F. Ying, ˝Immune interventions in stroke˝, Nat. Rev. Neurol., vol. 144, 2015.
[61] A. Szymanska, ˝Minocycline and intracerebral hemorrhage: Influence of injury severity and delay to treatment˝, Exp. Neurol., vol. 197, pp. 189-196, 2006.
[62] S. Massberg, ˝Fingolimod and sphingosine-1-phosphate — modifiers of lymphocyte migration˝, N. Engl. J. Med., vol. 355, pp. 1188-1191, 2006.
[63] Y. Lee, ˝Therapeutically targeting Neuroinflammation and microglia after acute ischemic stroke˝. BioMed Research International, vol. 2014, p. 9, 2014.
[2] A. Arauz, ˝Enfermedad Cerebral Vascular˝, Revista de la Facultad de Medicina de la UNAM, vol. 55, no. 3, pp. 11-21, 2012.
[3] J. Rong, ˝Role of inflammation and its mediators in acute ischemic stroke˝, J Cardiovasc Transl Res., vol. 6, no. 5., 2013.
[4] OMS/OPS, “Sistema de información regional de mortalidad 2014˝, World Health Organization, Geneva, 2014.
[5] SINAVE/DGE/, “Perfil Epidemiológico de las Enfermedades Cerebrovasculares en México”, 2012.
[6] A. Go, “Heart Disease and Stroke Statistics—2014 Update A Report From the American Heart Association”, Circulation, vol. 129, pp.28-92, 2014.
[7] C. Smith, “The immune system in stroke: clinical challenges and their translation to experimental research”, J Neuroimmune Pharmacol., vol. 8, no. 4, pp. 867-87, 2013.
[8] R. Macrez, “Stroke and the immune system: from pathophysiology to new therapeutic strategies”, Lancet Neurol, vol. 10, pp. 471-80, 2011.
[9] M. Edwarson, ˝Ischemic Stroke prognosis in adults˝, UpToDate, 2016.
[10] A. Alexander, ˝Correlating lesion size and location to deficits after ischemic stroke˝, Behav. Brains. and. funct., vol. 6, no. 6, 2010.
[11] Y. Lee, ˝Therapeutically targeting neuroinflammation and microglia after acute ischemic stroke˝, BioMed Research International, vol. 2014, pp. 1-9, 2014.
[12] C. Benakis, ˝The role of microglia and myeloid immune cells in acute cerebral ischemia”, Front. in. Neuroscien., vol. 8, no. 461, 2015.
[13] C. Iadecola, ˝The immunology of stroke: from mechanisms to translation˝, Nat. Med., vol. 17, pp. 796-808, 2011.
[14] T. Shichita, ˝Post-ischemic inflammation in the brain˝, Front. Immun., vol. 3, no. 132, 2012.
[15] C. Iadecola, ˝Cerebral ischemia and inflammation”, Curr. Opin. Neurol., vol. 14, pp. 89–94, 2001.
[16] A, Chamorro, ˝The harms and benefits of inflammatory and immune responses in vascular disease˝, Stroke, vol. 37, pp. 291-293, 2006.
[17] X, Xu, ˝Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets˝, Curr. Med. Chem., vol. 21, no. 18, pp. 2076-97, 2014.
[18] H. Chu, Chu, “Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia”, J. Cereb. Blood Flow Metab., vol. 34, pp. 450–459, 2014.
[19] A. Dénes, “Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation”, Brain Behav. Immun, vol. 24, pp. 708–723, 2015.
[20] T. Yan, ˝Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke˝, Neurosci Bull., vol. 31, no. 6, pp. 717-734, 2015.
[21] B. Famakin, “The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review”, Age and Disease, vol. 5, no. 5, pp. 307-325, 2014.
[22] B. Obermeier, “Development, manteinance and disruption of the blood-brain barrier”, Nat. Med., vol. 19, no. 12, pp. 1584-1597, 2013.
[23] T, Chiba, “Pivotal roles of monocytes/macrophages in stroke”, Mediators Inflamm., vol. 10, pp. 1-10, 2013.
[24] T. Woodruff, “Pathophysiology, treatment, and animal and celular models of human ischemic stroke”, Molecular Neurodegeneration, vol. 6, no. 1, 2011.
[25] D. Amantea, ˝Rational modulation of the innate immune system for neuroprotection in ischemic stroke˝, Frontiers in Neuroscience, vol. 9, no. 147, 2015.
[26] D. Zierath, ˝The immunologic profile of adoptively transfered lymphocytes influences stroke outcomes in patients“, J. Neuroimmunol., vol. 15, no. 263, 2013.
[27] S. Cheng, ˝Regulatory T Cell in stroke: A new paradigm for immune regulation”, Clin. and. Develop. Immun., vol. 2013, p. 9, 2013.
[28] A. Liesz, “Regulatory T cells are cerebroprotective immunomodulators in acute experimental stroke”, Nat. Med., vol. 15, no. 2, pp. 192-199, 2009.
[29] C. Kleinschnitz, “Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature”, Blood, vol. 121, no. 4, pp. 679-691, 2013.
[30] B. Clausen, “Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice”. J Neuroinflammation, vol. 5, no. 46, 2003.
[31] K. Lamberstein, ˝Inflammatory biomarkers in blood of patients with acute brain ischemia˝, Journal of Cerebral Blood Flow & Metabolism, vol. 32, pp. 1677-1698.
[32] Y. Miao, ˝Potential Serum Biomarkers in the pathophysiological processes of stroke˝, Expert Rev. Neurother., vol. 14, pp. 174-185, 2014.
[33] D, Doll, ˝Cytokines: The role in stroke and potential biomarkers and therapeutic targets“, Aging and Disease, vol. 5, no. 5, pp. 294-306, 2014.
[34] G. Jickling, ˝Blood biomarkers of ischemic stroke˝, Neurotherapeutics, vol. 8, pp. 349–360, 2011.
[35] J. Montaner, ˝Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke˝, J Cereb Blood Flow Metab, vol. 23, pp. 1403-07, 2003.
[36] S. Sotgiu, ˝Inflammatory biomarkers in blood of patients with acute brain ischemia˝, Eur J Neurol., vol. 13, pp. 505-13. 2006.
[37] C. Smith, ˝Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity adn long-term outcome˝, BMC Neuro. vol. 4, no. 2, 2004.
[38] C. Sommer, ˝Histology and infarct volume determination in rodent models of stroke˝, Rodent Models of Stroke, vol. 47, 2010.
[39] A. Chamorro, “Infection After Acute Ischemic Stroke. A Manifestation of Brain-Induced Immunodepression”, Stroke, vol. 38, pp. 1097-1103, 2007.
[40] S. Aslanyan, “Pneumonia and urinary tract infection after acute ischaemic stroke: a tertiary analysis of the GAIN international trial”, Eur. Jour. of Neur., vol. 11, pp. 49-53, 2004.
[41] B. Ovbiagele, “Frequency and Determinants of Pneumonia and Urinary Tract Infection During Stroke Hospitalization”, J. Stroke. Cerebrovasc. Dis., vol. 15, pp. 209-213, 2006.
[42] C. Meisel, “Central nervous system injury-induced immune deficiency syndrome”, Nat. Rev. Neuros., vol. 6, pp. 775-86, 2005.
[43] X. Urra, “Harms and Benefits of Lymphocyte Subpopulations in Patients with Acute Stroke”, Neurosci. J,, vol. 158, pp. 1174-1183, 2009.
[44] P. Li, “Adoptive Regulatory T-Cell Therapy Protects Against Cerebral Ischemia”, Ann. Neurol., 2013.
[45] K. Becker, “Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome”, Stroke., vol. 42, pp. 2763-2769, 2011.
[46] U. Dirnagl, “Stroke-induced immunodepression. Experimental evidence and clinical relevance”, Stroke, vol. 38, pp. 770-773, 2007.
[47] B. Famakin, “The Immune Response to Acute Focal Cerebral ischemia and Associated Post-stroke Immunoderession: A Focused Review”, Aging. Dis., vol. 5, pp. 307-326, 2014.
[48] R. Shim, “Ischemia, Immunosuppression and Infection—Tackling the Predicaments of Post-Stroke Complications”, Int. J. Mol. Sci., vol. 17, 2016.
[49] K. Prass, "Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation", J. Exp. Med., vol. 1, pp. 752-83, 2003.
[50] A. Chamorro, “The Early Systemic Prophylaxis of Infection After Stroke Study. A Randomized Clinical Trial”, Stroke., vol. 36, pp. 1495-1500, 2005.
[51] H. Harms, “Preventive Antibacterial Therapy in Acute Ischemic Stroke: A Randomized Controlled Trial”, PLoS One., vol. 3, 2008.
[52] H. Harms, “Influence of Stroke Localization on Autonomic Activation, Immunodepression, and Post-Stroke Infection”, Cerebrovasc. Dis., vol. 32, pp. 552-560, 2011.
[53] W. Westendrop, “The Preventive Antibiotics in Stroke Study (PASS): a pragmatic radomised open-label masked endpoint clinical trial”, Lancet., 2015.
[54] T. Dziedzic, “Beta-blockers reduce the risk of early dead in ischemic stroke” J. Neurol. Sci., vol. 252, pp. 53-56, 2007.
[55] C.H. Wong, “Functional innervation of hepatic iNKT cells is immunosuppressive following stroke”, Science, vol. 334, pp. 101-105, 2011.
[56] S. Lenglet, “Recombinant tissue plasminogen activator enhaces microglial cell recruitment after stroke in mice”. jou of cbf and metabolism (2014) 34, 802-812
[57] E.C. Jauch, ˝Guidelines for the early management of patients with acute ischemic stroke˝, Stroke, vol. 44, pp. 870-947, 2013.
[58] C.J. Siao, ˝Cell-type specific roles for tissue plasminogen activator realeased by neurons or microglia after excitotoxic injury˝, J. Neurosci., vol. 23, pp. 3234-3242, 2003.
[59] A. Reijerkerek, ˝Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier˝, J. Immunol. vol. 181, pp. 3567-3574, 2008.
[60] F. Ying, ˝Immune interventions in stroke˝, Nat. Rev. Neurol., vol. 144, 2015.
[61] A. Szymanska, ˝Minocycline and intracerebral hemorrhage: Influence of injury severity and delay to treatment˝, Exp. Neurol., vol. 197, pp. 189-196, 2006.
[62] S. Massberg, ˝Fingolimod and sphingosine-1-phosphate — modifiers of lymphocyte migration˝, N. Engl. J. Med., vol. 355, pp. 1188-1191, 2006.
[63] Y. Lee, ˝Therapeutically targeting Neuroinflammation and microglia after acute ischemic stroke˝. BioMed Research International, vol. 2014, p. 9, 2014.
Publicado
2017-03-27
Sección
Ciencias de la Salud
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