ISCHEMIA-REPERFUSION INJURY

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ISCHEMIA-REPERFUSION INJURY
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What is ischemia-reperfusion injury?
After prolonged ischemia, reestablishment of
blood flow does not relieve ischemic injury,on
the contrary aggravates the tissue injury
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In the definition of ischemia-reperfusion
injury

• 3 Key points are
• After ischemia for a long time
• Reestablishment of blood flow
• More severe injury

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Which factors are involved in reperfusion
injury

• Generally speaking,
• Duration of ischemia the longer period
  of ischemia, the more severe injury
• Severity of ischemia the more
  grievous ischemia, the more severe injury
• Speed of reperfusion the faster
  reperfusion of blood, the more severe injury
• Ischemia preconditioning increasing tolerance
  to reperfusion injury

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Why are more severe injury induced by
reestablishment of blood flow after ischemia?

1. MICROVACULAR DAMAGENO-Reflow Phenomenon

• Vaso-endothelial edema
  ATP depletion ?
  decreased Na-K pump function ? Na and
  water ? entering cell ? endorthelial edema
• Vaso-endothelial damage
  WBC
  adherence ? OFR increase and NO decrease
• Microvascular obstruction
  
  Squeeze of the coronary arteries induced by
  ischemic myocardium and by interstital
  edema of myocardium
  Adherence, Aggregation and Activation of WBC

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2. The Role of Leukocyte

• Blocking microvasculature in the region
  of reperfusion
• Adhering to microvascular endothelium
  through interaction between L-selectin on
  surface of WBCand ICAM-1 on surface of
  endothelium
• Damaging tissues and cells in the region
  of reperfusion through releasing arachidonic
  acid (AA) ? TXA2, lysosomal enzymes etc. And
  producing OFR in respiratory burst.

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Damaged endothelium NO decrease CAMs
upregulation L-selectin ICAM-1 WBC ADHERENCE
to ENDOTHELIUM Releasing OFR, TXA2,

lysosomal enzymes Blocking blood
flow Damaging tissues and cell
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• Calcium Overload
  Intracellular calcium
  concentration abnormally increases and leads to
  cell and tissue damages

• How to maintain Intracellular calcium
• at normal level?
• Ca2 Pump on cell membrance
• Na - Ca2 exchage pump
• Ca2 Pump on mitochondrial membrane
• Ca2 Pump on endoplasmic reticulum

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• Why dose calcium overload occur
• during reperfusion
• Depleted energe
• Increased permeability of cellular
• membrance
• Increased intracellular sodium

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• What are effects of calcium overload
• Damage mitochondria ?
• ATP production decrease
• Cause myocardial injury ?
• contraction weakness
• promote OFR formation ?
• damege aggravation

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• Role of
• Oxygen Free Radical
• OFR species
• O2. (superoxide anion radical)
• OH. (hydroxyl radical)
• 1O2 (single oxygen)

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OFR sources mitochondria, catecholamine
autooxidation xanthine oxidase, activated wbc
and so on. OFR production In
ischemia-reperfusion injury a large amount
of OFR is produced.
ATP ?ADP ?AMP ?Adenosine ?Inosine ? Hypoxanthine
(ISCHEMIA) Xanthine dehydrogenase (XD)
Protease Ca 2
Xanthine oxidase (XO) (REPERFUSION) O.2
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Destructive effects of OFR

• Attacking membrane structure such as
  mitochondria membrane ? interfering with
  energy metabolism
• Attacking DNA ? changing genetic information
  ? cell death
• Initiating lipid peroxidation ? increasing
  permeability of membrane and inducing
  destruction of membrane ? cell death
• Destroying proteins ? decreased enzyme
  activity ? metabolic disorder

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Excess oxygen
Neutrophil Free radicals
infiltration ?
?
ISCHEMIAREPERFUSION INJURY
? ?
Microvascular damage Calcium overload
Major mechanisms of ischemia-
reperfusion injury
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1.Vasomotor Responses OFR
Calcium Overload WBC ?
? ?
Damaged endothelium ?
? NO, PGI2 release?
TXA2,ET release? ?
? VASOCONSTRICTION
?
Aggravating injury

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OFR Calcium Overload
WBC Damaged endothelium
Vascular Sticking
WBC Liable to form permeability?
platelets to endothelium thrombosis
Edema Releasing OFR
Blocking blood
proteolytic enzymes flow
Aggravating injury
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Excess Oxygen Neutrophil
Microvascular Calcium Free radicals
infiltration damage
overload ? ?
? ?
ISCHEMIAREPERFUSION INJURY ?
? ? ?
Heart Brain Liver
Intestine ? ?
? ? Shock
Cytotoxic Jaundice Mucosal
Pump failure edema Enlargement
necrosis Arrhythmia Neuron death GTP?
Ulceration
Hemorrhage
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How to prevent and treat
ISCHEMIAREPERFUSION INJURY ? Relieving
ischemic condition as a prerequisite Excess
Oxygen Calcium
Neutrophil Free radicals overload
infiltration ?
? ? ISCHEMIA-REPERFUS
ION INJURY ?
? ? OFR
Calcium WBC Scavenger
Antagonist Antiboby