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Brain edema23

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This slideshow was presented in the advanced critical care physiology class at Sina Hospital, Tehran University of Medical Sciences

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Brain edema23

  1. 1. MOLECULAR PATHOBIOLOGY OF BRAIN EDEMA IN NEUROLOGICAL INJURY ADVANCED CRITICAL CARE PHYSIOLOGY CLASSES, TUMS Reza Nejat, M.D. Anesthesiologist, FCCM former-Assistant Professor, SBMU
  2. 2. Pathobiology of Brain Edema  Cerebral ischemia/reperfusion and traumatic injuries result in:  sequences of metabolic impairment,  energy failure  mediator interactions such as glutamate release and glutamate receptor activation Advanced Critical Care Physiology Classes
  3. 3. Pathobiology of Brain Edema  Mediator interactions such as glutamate release and glutamate receptor activation:  excitotoxicity,  elevated intracellular calcium concentration,  mitochondrial dysfunction,  intracellular chaotically enzymatic interactions,  free radical production,  chaotic intrinsic nitric oxide production,  activation of apoptosis cascade,  inflammatory reactions. Advanced Critical Care Physiology Classes
  4. 4. Pathobiology of Brain Edema Cerebral edema: a clinicopathological state characterised by an increase in brain water content (> 80%) Advanced Critical Care Physiology Classes
  5. 5. Pathobiology of Brain Edema  Four Fluid Compartments:  Brain-blood (cerebral vessels),  Cerebrospinal fluid (CSF) (ventricular system),  Interstitial fluid (brain parenchyma)  Intracellular fluid (neurons and glial  cells) Advanced Critical Care Physiology Classes
  6. 6. Pathobiology of Brain Edema Cerebral Edema: Vasogenic Cytotoxic/ionic/cellular Interstitial/hydrocephalic Osmotic/hypostatic Hydrostatic Advanced Critical Care Physiology Classes
  7. 7. Pathobiology of Brain Edema Cerebral Edema: Vasogenic: (the most common form) primarily due to the breakdown of BBB secondary to mechanical disruption: brain trauma, acute malignant hypertension, radiation chemical mediators: tumours, inflammation and infection Advanced Critical Care Physiology Classes
  8. 8. Pathobiology of Brain Edema Cerebral Edema: Cytotoxic/ionic/cellular: BBB intact Cellular Energy Failure Disrupted Ionic Pumps Anaerobic metabolism GNT Advanced Critical Care Physiology Classes
  9. 9. Pathobiology of Brain Edema Cerebral Edema: Interstitial/hydrocephalic: Intraventricular pressure increases: breakdown of ventricular ependymal lining transependymal migration of CSF into extracellular space Advanced Critical Care Physiology Classes
  10. 10. Pathobiology of Brain Edema Cerebral Edema: Osmotic/hypostatic:  Imbalance of osmolality between serum plasma and brain parenchyma  Salt intoxication  Water intoxication  cellular and BBB integrity is maintained  SIADH, TBI with hypo-osmolal serum Advanced Critical Care Physiology Classes
  11. 11. Pathobiology of Brain Edema Cerebral Edema: Hydrostatic: Arterial pressure exceeds the upper limit of autoregulation There is venous congestion (head-down position, pressure on the jugular veins, high intrathoracic pressure). Advanced Critical Care Physiology Classes
  12. 12. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  13. 13. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  14. 14. Pathobiology of Brain Edema Cerebral Edema: Vasogenic: (the most common form) primarily due to the breakdown of BBB secondary to mechanical disruption: brain trauma, acute malignant hypertension, radiation chemical mediators: tumours, inflammation and infection Advanced Critical Care Physiology Classes
  15. 15. Pathobiology of Brain Edema  BBB consists of endothelial cells, TJ, basement membrane and foot processes of astrocytes.  BBB to fulfill its function normally:  “neurovascular unit” should act in concert:  cerebral microvasculature endothelial cells,  neurons,  extracellular matrix,  astrocytes and pericytes Advanced Critical Care Physiology Classes
  16. 16. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  17. 17. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  18. 18. Pathobiology of Brain Edema  Lipophilic molecules pass through BBB easily  Ions and small molecules like glucose and amino acids are transported through specific channels and carriers  Large molecules such as peptides and proteins are conducted via:  Endocytosis  transcytosis  hiring caveolae and clathrin-coated microvesicles Advanced Critical Care Physiology Classes
  19. 19. Pathobiology of Brain Edema  Integrity of BBB:  Depends on the tight junctions (TJ) located between the endothelial cells of brain capillaries. Advanced Critical Care Physiology Classes
  20. 20. Pathobiology of Brain Edema  Astrocytes and pericytes induce endothelial cells to form the tight junctions Advanced Critical Care Physiology Classes
  21. 21. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  22. 22. Pathobiology of Brain Edema During BBB injury: Initially, an increase in caveolae Later, tight junction breakdown Finally, endothelial cell injury  Caveolae: plasmalemmal vesicles which allow protein passage through fluid-phase transcytosis or transendothelial channels Advanced Critical Care Physiology Classes
  23. 23. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  24. 24. Pathobiology of Brain Edema  Brain injuries exacerbate the leakiness of BBB:  raising paracellular diffusion through degraded TJs,  increasing formation and mobilization caveolae  boosting transcytosis Advanced Critical Care Physiology Classes
  25. 25. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  26. 26. Pathobiology of Brain Edema  BBB malfunction follows a biphasic temporal course:  an early phase of high permeability  a more prolonged delayed phase of leakiness. Advanced Critical Care Physiology Classes
  27. 27. Pathobiology of Brain Edema  Disintegration of BBB:  inflammatory mediators,  reactive oxygen species (ROS),  VEGF,  matrix metalloproteinases (MMPs)  microRNAs Advanced Critical Care Physiology Classes
  28. 28. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  29. 29. Pathobiology of Brain Edema  BBB injury results in: Activation of glial cells Production of various mediators:  bradykinin, serotonin, histamine, complement, arachidonic acid, NO and leucotrienes The movement of protein rich exudates into extracellular space  White matter is more affected Advanced Critical Care Physiology Classes
  30. 30. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  31. 31. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  32. 32. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  33. 33. Pathobiology of Brain Edema  Cerebral blood flow<20ᶜᶜ/min/100g results in:  Disturbance of Na⁺-K⁺-ATPase pump  Inward flow of Na⁺↑  ↑Inward flow of water, H⁺, HCO3⁻, Ca⁺⁺  Outward flow of K⁺↑ Advanced Critical Care Physiology Classes
  34. 34. Pathobiology of Brain Edema ASTROCYTES Advanced Critical Care Physiology Classes
  35. 35. Pathobiology of Brain Edema  Astrocytes are highly branched cells:  Juxtaposed to the soma, dendrites and axons of neurons, the plasma membrane of microglial cells, oligodendrocytes, and other astrocytes,  can potentially influence and be influenced by a large number of cells, synapses, and vascular structures  harbor virtually all of the constitutive metabolic enzymes, especially glutamine synthetase and pyruvate carboxylase  Involved in the metabolism of glucose, ammonia, and glutamate Advanced Critical Care Physiology Classes
  36. 36. Pathobiology of Brain Edema  Astrocytes:  take up, metabolize neurotransmitters,  buffer changes in ECF ion concentration,  serve as intermediates in the cross talk between neurons and blood vessels  Express iGluRs and mGluRs  Express 𝑲𝑲⁺𝑪𝑪𝑪𝑪⁺⁺ channels Advanced Critical Care Physiology Classes
  37. 37. Pathobiology of Brain Edema  Astrocytes; pivotal role in:  Axonal Growth  Energy Metabolism  Neurotransmitter Homeostasis  Water/Electrolyte Balance  Immune Response Advanced Critical Care Physiology Classes
  38. 38. Pathobiology of Brain Edema  Astrocytes are highly branched cells:  Rich in receptors of neurotransmitters, growth factors, cytokines, and chemokines, transporters for numerous molecules:  K⁺, water, glutamate, glutamine, glucose, ketone bodies and lactate,  can change (transform) their phenotype and proliferate in response to certain (usually damaging) conditions. Advanced Critical Care Physiology Classes
  39. 39. Pathobiology of Brain Edema  𝑮𝑮𝑮𝑮 𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮 + 𝑵𝑵𝑵𝑵𝟑𝟑 + 𝑨𝑨𝑨𝑨𝑨𝑨 = 𝑮𝑮𝑮𝑮 𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮 𝑮𝑮𝑮𝑮 + 𝑨𝑨𝑨𝑨𝑨𝑨 + 𝑷𝑷𝒊𝒊  rapid metabolism of IC glutamate is a prerequisite for efficient glutamate clearance from the extracellular space  Elevated concentrations of EC glutamate and glutamate analogues in the brain can lead to hyperexcitability, seizures and neuronal death Advanced Critical Care Physiology Classes
  40. 40. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  41. 41. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  42. 42. Pathobiology of Brain Edema During normal and abnormal neuronal activity, there is cotransport of 3Na+, 1Cl−, 1H+ and antiport 1K+ ion per glutamate molecule along with water molecule. Advanced Critical Care Physiology Classes
  43. 43. Pathobiology of Brain Edema  GNT  During ischaemia/hypoxia, energy dependent pathways fail and glutamate accumulates to toxic levels and abnormal surge of neuronal activity happens through activation of :  N-methyl-D-aspartate (NMDA) R,  AMPA R,  mGlu R  Kinate R Advanced Critical Care Physiology Classes
  44. 44. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  45. 45. Pathobiology of Brain Edema  GNT  NMDA (N-methyl D-aspartic acid) Receptor  Non-NMDA Receptor  AMPA Receptor  Kianate Receptor  mGluR  Na⁺ and Cl⁻ influx resulting in Ca⁺⁺ influx  NMDA receptor-mediated K⁺ efflux Advanced Critical Care Physiology Classes
  46. 46. Pathobiology of Brain Edema  GNT  Na⁺ and Cl⁻ influx resulting in Ca⁺⁺ influx  Ca⁺⁺ influx & ROS generation (oxidative stress)  Ca⁺⁺ dependent conversion of XDH to XOD  Allowing H₂O₂ and O₂⁻• production  Ca⁺⁺ activated PLA₂ and NOS  NMDA receptor-mediated K⁺ efflux resulting in neuronal apoptosis Advanced Critical Care Physiology Classes
  47. 47. Pathobiology of Brain Edema  GNT  ROS production due to NMDA activation  Uncoupling of MTC  Leakage of electron from respiratory chain in MTC  Arachidonic acid metabolism by oxidases  Inactivation of PFK, LDH, CPKinas  Depletion of anti-oxidant capacity of the cell Advanced Critical Care Physiology Classes
  48. 48. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  49. 49. Pathobiology of Brain Edema The time course of ROS production in GNT:  Early phase (up to 30 min)  Later phase (3-24 h) Advanced Critical Care Physiology Classes
  50. 50. Pathobiology of Brain Edema  Early Phase:  Glutamate binding to receptor;  Calcium influx in cytosol;  XDH→XOD conversion;  ROS production;  ROS-induced cyt c release;  Cyt c as ROS scavenger;  Cyt c as electron donor;  Cyt c-dependent energy generation. Advanced Critical Care Physiology Classes
  51. 51. Pathobiology of Brain Edema  Late Phase:  Glucose uptake increase;  Increase in lactate production via glycolysis;  Mitochondrial shuttle impairment;  NADH oxidation via mitochondrial  NADH-b5-oxidoreductase;  Massive ROS production by mitochondria;  Mitochondrial permeability transition. Advanced Critical Care Physiology Classes
  52. 52. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  53. 53. Pathobiology of Brain Edema  Hypoxia/Ischemia:  Increases transcription of hypoxia-inducible factor 1 (HIF-1) gene.  HIF-1, activates hypoxia-responsive element (HRE) in the genome,  HRE, a transcription factor regulates the transcription of:  multiple genes encoding EPO, vascular endothelial growth factor (VEGF) and platelet derived growth factor,  over 100 other HIF responsive genes including those involved in cell metabolism encouraging anaerobic production of ATP, in addition to cell, survival, proliferation and migration and vasodilation. Advanced Critical Care Physiology Classes
  54. 54. Pathobiology of Brain Edema  HIF-1α dependent signaling pathways might also be a source of neuroinflammation/apoptosis and hence BBB dysfunction.  HIF-1α in hypoxic brain insult increases expression of VEGF, VEGFR, MMP-9 and AQP-4  Astrocytes and pericytes produce VEGF and MMPs Advanced Critical Care Physiology Classes
  55. 55. Pathobiology of Brain Edema  MMPs:  belong to a 25-member family of zinc- dependent endopeptidases  secreted in an inactive form in untraceable or in a very delicately controlled low concentration in the adult healthy brain.  contribute to degrading the extra- cellular matrix (ECM). Advanced Critical Care Physiology Classes
  56. 56. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  57. 57. Pathobiology of Brain Edema  MMPs:  several significant physiological potentials involved in:  growth,  development,  tissue repair and wound healing  synaptic plasticity  neurite growth  myelinogenesis. Advanced Critical Care Physiology Classes
  58. 58. Pathobiology of Brain Edema  MMPs:  up-regulated and activated in ischemic and other brain injuries,  Its latent form is activated by:  Endogenous and exogenous plasminogen activator  Furin  free radicals Advanced Critical Care Physiology Classes
  59. 59. Pathobiology of Brain Edema  AQP-4  integral membrane proteins which play important roles in mediating water homeostasis and bidirectional passive trans- cellular water transfer in response to osmotic gradient.  the expression of this channel is modulated by HIF-1 and VEGF Advanced Critical Care Physiology Classes
  60. 60. Pathobiology of Brain Edema  AQPs in the CNS contribute to:  Glymphatic (Glial Lymphatic) pathway:  couples cerebrospinal fluid (CSF) influx to interstitial spinal fluid (ISF) efflux  through convective bulk flow from peri- arterial to peri-venous spaces (Virchow- Robin spaces) in microvasculature of the brain Advanced Critical Care Physiology Classes
  61. 61. Pathobiology of Brain Edema  AQPs are involved in:  potassium buffering,  waste material clearance,  neuroinflammation,  osmosensation,  astroglial cell migration,  Ca signaling,  neural signal transduction,  long-term plasticity,  spatial memory,  cell adhesion,  regulating cerebral edema Advanced Critical Care Physiology Classes
  62. 62. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  63. 63. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  64. 64. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  65. 65. Pathobiology of Brain Edema AQP-4 expression has an impact on BBB integrity *Cytotoxic edema-induced vasogenic edema Advanced Critical Care Physiology Classes
  66. 66. Pathobiology of Brain Edema  Vascular endothelial cell growth factors (VEGF), a family of cytokines, induce angiogenesis through proliferation, sprouting, migration of the endothelial cells and new tube formation by these cells.  Found in pericytes in the border of brain lesions  After binding withVEGFR-2 increases vascular permeability through activating cGMP and a NO-dependent pathway Advanced Critical Care Physiology Classes
  67. 67. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  68. 68. Pathobiology of Brain Edema  VEGFs may be inactivated:  when they bind with heparan sulfate proteoglycan (HSPG) moieties of the ECM or  are trapped by a secreted isoform of VEGF receptors (sVEGF-R)  MMPs may split the bound form of VEGF  VEGF may be destructed by proteases (like MMPs) Advanced Critical Care Physiology Classes
  69. 69. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  70. 70. Pathobiology of Brain Edema Advanced Critical Care Physiology Classes
  71. 71. EKG Advanced Critical Care Physiology Classes
  72. 72. Fundamentals of EKG Thanks for your patience Advanced Critical Care Physiology Classes

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