Ischemia-reperfusion Injury

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Ischemia-reperfusion Injury
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Contents

1. Concepts Ischemia-reperfusion (I-R) injury,
   oxygen/calcium/pH paradox, calcium overload,
   no-flow phenomenon
2. Causes and conditions of I-R injury
3. Mechanisms of I-R injury
4. Metabolic and functional alterations
5. Prevention and treatment principle

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Reperfusion Injury
Aggravated ischemic injury during reperfusion
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Ischemia Components
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Ischemic Injury of Neurons
0 hr
1 hr
2 hr
Reperfusion
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Injury Windows
Ischemia
Death
Injury
Time
Reperfusion
Oxygen paradox, calcium paradox, pH paradox
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Causes and Conditions of Reperfusion Injury
Recover from cardiac arrest Organ
transplantation Lysing thrombi
Causes
Ischemia time Branch circulation Oxygen
consumption Temperature, Na, pH, Ca2
Conditions
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Case Presentation
A 50-year-old man was admitted to the hospital
with severe chest pain of 5 hours duration.
Mental confusion and in acute dyspnea.
Diuretic, tissue plasminogen activator
HR 110 beats/min, sinus rhythm BP
75/50 mmHg ECG ST segment elevation,
V1-V6 LVEF 31
Improvement in breath BP 100/70 mmHg LVEF
38 Temporary ventricular tachycardia
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Balloon angioplasty
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Mechanisms of Reperfusion Injury
?Free radicals ?Ca2i Neutrophil activation and
Others
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Free radical Any atom or molecule possessing
unpaired electrons
Superoxide anion (O2.-) Hydroxyl radical
(OH.) Nitric oxide (NO.) Peroxynitrite (ONOO- )(
??????) Lipid peroxide radical (LOO.)
Oxygen free radicals
Oxygen free radicals Hydrogen peroxide Others
Reactive oxygen species (ROS)
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Formation of ROS
1. Mitochondria
2. Activated inflammatory cells
3. Nitric oxide
4. Ionizing radiation
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Mechanism 1
Reperfusion
? Ca2i
O2
ROS
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Mechanism 2
Ischemia
O2?
ATP
Xanthine dehydrogenase
?Ca2i
? AMP
? Xanthine oxidese
O2.- H2O2
?Hypoxanthine
xanthine
Reperfusion
O2
Uric acid
Endothelial cell
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Mechanism 3
Ischemia
Reperfusion
Pro-inflammatory mediators (e.g. cytokines)
O2
NO
O2.-
ONOO-
(Respiration burst)
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Biochemical Impacts of ROS
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Calcium Overload
The abnormal increase of intracellular calcium
which causes cell injury
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Mechanism 1
Ischemia
? ATP Membrane depolarization
?Na
Reperfusion
Na/Ca exchanger
Ca2
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Mechanism 2
Ischemia
Reperfusion
?H
?H
H
Na
? Na
Na/H exchanger
? Ca2
Ca2
Na
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Mechanism 3
Ca2
Ca2
SR
IP3
H
DG
PKC
Na
Na
a1
NA
PLC
PI
Reperfusion
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Mechanism 4
Reperfusion
Mitochondria
?Ca2
ER SR
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Neutrophil Activation and Others
?Nai Gene activation Neutrophil activation

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Role of Neutrophil
Reperfusion
Neutrophil activation
ROS
Inflammatory mediators
Injury of Micro-vessels
No-reflow phenomenon
Cell injury
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Structural and Functional Changes
Reperfusion arrhythmia Myocardial stunning
Heart
Edema Cell death
Brain
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Electrocardiographic Alterations Associated with
the Three Zones of Myocardial Infarction
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Heart Injury
Ischemia-reperfusion injury
Calcium overload Free radical
Destroy of contractile protein
Ca K Na
Myocardial stunning
Arrhythmia
Cell death
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Brain Injury
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Principles of Prevention and Treatment
Control of reperfusion conditions Removal of free
radicals Use of calcium antagonists Use of cell
protection reagents Treatment of edema
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Removal of ROS
GSH
H2O
OH.
SOD
TOH
LOOH
LOO.
O2.-
ONOO-
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Thank you