ischemia-reperfusion injury (iri)

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Ischemia-reperfusion injury (IRI) Chapter 10 Department of Pathophysiology, Anhui Medical University Yuxia Zhang

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Chapter 10. Ischemia-reperfusion injury (IRI). Yuxia Zhang. Department of Pathophysiology, Anhui Medical University. Contents. Concepts: IRI, oxygen/calcium/pH paradox Causes and conditions of IRI Mechanisms of IRI injury Metabolic and functional alterations - PowerPoint PPT Presentation

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Page 1: Ischemia-reperfusion injury (IRI)

Ischemia-reperfusion injury (IRI)

Chapter 10

Department of Pathophysiology, Anhui Medical University

Yuxia Zhang

Page 2: Ischemia-reperfusion injury (IRI)

Concepts: IRI, oxygen/calcium/pH paradox

Causes and conditions of IRI

Mechanisms of IRI injury

Metabolic and functional alterations

Prevention and treatment principle

Contents

Page 3: Ischemia-reperfusion injury (IRI)

Introduction• at 1960 , Jenning:MI/R I

• 1968, brain ; 1972, kindey ; 1978, lung ; 1981, intestinal ; and so on

• Clinical phenomenon: bypass surgery,shock treatment,organ transplantation, thrombolysis, recovery of hearts after ischemic arrest , Percutanueous Transluminal Coronary Angioplasty (PTCA)

• I/R I is a common phenomenon

• paradoxical phenomenon

Page 4: Ischemia-reperfusion injury (IRI)

1.Concept

IRI

the reestablishment of blood flow after prolonged ischemia aggravates the tissue damage.

Page 5: Ischemia-reperfusion injury (IRI)

pH paradox

ischemia acidosis , disorder of function and metbolism on cell severe IRI pH paradox

calcium paradox

pre-perfuse rat heart with no calcium perfusion for 2min perfuse calcium perfusion, cell release enzyme myofibril over-constract, electron signals abn

ormal , calcium paradox

Page 6: Ischemia-reperfusion injury (IRI)

Oxygen paradox

Hypoxia liquid perfuse organ or culture without oxygen

injury

restore perfusion severe injury

Page 7: Ischemia-reperfusion injury (IRI)

2. Cause of ischemia-reperfusion injury and affecting factor

Recover from cardiac arrest

Organ transplantation

Lysing thrombi

( 1 ) cause

Page 8: Ischemia-reperfusion injury (IRI)

( 2 ) Affecting factor

Duration of ischemia

small animals 5-10min: arrhythmia

20-30min: ventricular tremor

big animals20-40min: reversible injury

40-60min:irreversible injury

diversity between small and big animal

Page 9: Ischemia-reperfusion injury (IRI)

Branch circulation : chronic

O2 consumption rate

[K+ ], [Mg2+]condition of reperfusion

T, pressure,pH,Na+,Ca2+

protection

T, pressure,Na+,Ca2+ damage

Page 10: Ischemia-reperfusion injury (IRI)

 

3. Mechanisms of IRI

• role of oxygen free radical

• calcium overload

• role of leukocyte

Page 11: Ischemia-reperfusion injury (IRI)

(1)Role of oxygen free radical

concept and classification of free radicalconcept and classification of free radicalFree radical: Any atom or molecule possessing unpaired electrons

Nitric oxide (NO.)Peroxynitrite ( ONOO- )Cl• 、 CH3

• 、 NO

Free radicals

Oxygen free radicals(OFR)

Superoxide anion (O2.-),

Hydroxyl radical (OH.):

Lipid peroxide radical ˉ

: LL•• LO LO •• LOO LOO ••

Others :

Reactive oxygen species (ROS) : OO22• • OHOH• • 11OO22 H H22OO22

Page 12: Ischemia-reperfusion injury (IRI)

 formation of oxygen free radical 

nature oxidation of Hb , Cyt C

O2 O ‾∙2 H2O2 OH∙ H2O

H2O

oxidation of enzyme :XO

Mitochondria:

normal: O2+4e+4H+→H2O+ATP

abnormal :O2+e→ O·-2 +e +2H+

→H202+e+H+→ OH· +e+H+

→H20

O ‾∙2

Page 13: Ischemia-reperfusion injury (IRI)

SOD O·-

2+ O·-2+2H+ H2O2+O2

O·-2+H2O2 OH· + OH·+O2

Fenton Haber-Weiss : SOD Fe2+ Fe3+

O·-2 H2O2 OH· + OH-

Production of OH·

Page 14: Ischemia-reperfusion injury (IRI)

Mechanism of increased OFR generationMechanism of increased OFR generationXanthine oxidase pathwayXanthine oxidase pathway :: XO↑XO↑

normal : Endothelial cell , XO 10% , XD 90%

OHOH••

xanthinexanthine++OO2 2 ••+H+H22OO22

– – hypoxanthinehypoxanthine

isch

emia

isch

emia

reperfusionreperfusion

Uric acid+OUric acid+O2 2 •• +H+H22OO22

ATPATP

ADPADP

AMPAMP

XDXD

CaCa2+2+

XOXO

O2 O2

Page 15: Ischemia-reperfusion injury (IRI)

The effects of leucocyteThe effects of leucocyte :: respiratory burstrespiratory burst

NADPH oxidase NADPH oxidase NADPH +2O2

2O·-2 +NADP++H+

NADH+O2 H2O2+NAD+ + 2H+NADH oxidase NADH oxidase

reperfusion : oxygen consumption of infiltrated

WBC:↑70-90% O2

Page 16: Ischemia-reperfusion injury (IRI)

Disfunction of mitochondria  

normal: O2+4e+4H+→H2O+ATP

abnormal :O2+e→ O·-2

+e +2H+→H202+e+H+

→OH· +e+H+→H20

catecholamine autooxidation  

AD adsenale+ O·-2

MAO

Page 17: Ischemia-reperfusion injury (IRI)

Damage of oxygen-derived free radicalsDamage of oxygen-derived free radicals

membrane lipid peroxidation

cellular membranelipid peroxidation

permeability↑fluidity↓

[Ca2+] i

calcium calcium overloadoverload

[Na+] i , [Ca2+] i

lipid cross-linked

inhibition of Na+-pump and Ca 2+ -pump

Page 18: Ischemia-reperfusion injury (IRI)

membrane lipid peroxidation

phospholipase Cphospholipase D

PGs , LTsTXA2

damage of mitochondria membrane

ATP

Page 19: Ischemia-reperfusion injury (IRI)

  enzymes :

channels:

inhibition of protein function

destruction of nuclear acid

base hydroxylation 、 breakdown of DNA

Page 20: Ischemia-reperfusion injury (IRI)

HEALTHY CELL (left) | FREE RADICAL DAMAGE (right)

Page 21: Ischemia-reperfusion injury (IRI)

The abnormal increase of intracellular calcium

which causes cell injury

(2) Calcium overload

Concept

Metabolic pathway of [Ca2+]i

Ca 2+ pump in the cell membrane;

Na+-Ca2+ exchange pump in the cell membrane ;

Ca 2+ pump in the mito. membrane ;

Ca 2+ pump in endoplasmic reticulum

Page 22: Ischemia-reperfusion injury (IRI)

K+

Na+

3Na+

Ca2+

ATP↓

Na+↑Ca2+↑

Ischemia

mechanism of calcium overload

Reperfusion

Abnormal Na+-Ca2+ exchange

direct activation : intracellular sodium↑

Page 23: Ischemia-reperfusion injury (IRI)

indirect activation ( 1 ): intracellular 【 H+ 】↑

3Na+

Ca2+

Na+

K+

H+

Na+

ReperfusionH+↓

H+↑Na+↑

Ca2+↑

IschemiaH+↑

Page 24: Ischemia-reperfusion injury (IRI)

indirect activation ( 2 ): activation of PKC

ischemia NE α1 – receptor

NE

SR

myofilament

Page 25: Ischemia-reperfusion injury (IRI)

catecholamine β – receptor [Ca2+] i

β Cellular membrane

Ca2+ ↑

L Ca2+- channel

Page 26: Ischemia-reperfusion injury (IRI)

Damage of mitochondria

damage of cellular membrane:

injury of biomembrane

[Ca2+ ] ↑

ATP

Ca 2+ - ATPasecalcium overload

Damage of mitochondria and sarcoplasmic

Damage ofSarcopasmic

Page 27: Ischemia-reperfusion injury (IRI)

Pathogenesis of calcium overload

Damage mitochondria : ATP ↓

promote OFR formation : damege aggravation

Stimulating the phospholipase  : injury of

membrane cell and cell organ 

mitochondrial dysfunction

Page 28: Ischemia-reperfusion injury (IRI)
Page 29: Ischemia-reperfusion injury (IRI)

(3) role of leukocyte

activation,margination and aggregation of

PMNs after reperfusion

adhesion molecule ;chemotatic factor;mediators of inflammation

Page 30: Ischemia-reperfusion injury (IRI)

Neutrophil activation

ROS Inflammatorymediators

Injury of Micro-vessels

No-reflow phenomenonCell injury

Role of Neutrophil

Reperfusion

Page 31: Ischemia-reperfusion injury (IRI)

Ischemia-reperfusion injury of heart

3. Changes of function and metabolism

Changes in cardiac function Decrease of myocardial contractility : myocardial stunning Eperfusion arrhythmia

Changes in myocardial metabolism: ATP↓,

ADP↑, AMP↑

Changes in myocardial structure: cell edma , contraction band , apoptosis

Page 32: Ischemia-reperfusion injury (IRI)

Heart InjuryHeart Injury

Ischemia-reperfusion injury

Calcium overload Free radical

Destroy of contractile protein

Myocardial stunning

Ca++ K+ Na+

Arrhythmia Cell death

Page 33: Ischemia-reperfusion injury (IRI)

Ischemia-reperfusion injury of brain ATP Na+-pump cellular edema

Hypoxia of cells cellular acidosis Excitability transmitter inhibitive transmitter cAMP↑ cGMP↓

activate free fatty acid↑ lipid peroxidation↑

Hisconstructure:Edema , necrosis

Page 34: Ischemia-reperfusion injury (IRI)

4. Principles of prevention and treatment

(1) restoring normal perfusion of tissue in time

low temperature;

low pressure;

low flow;

low natrium(sodium);

low pH;

low calcium

Page 35: Ischemia-reperfusion injury (IRI)

(2) improve the metabolism of the tissues

ATP; cytochrome C;

(3) sweep away free radical: VitE: lose e FR FR (lipid)

VitC: clear OH∙ (water)

β-cartenoids: clear 1O2

GSH

Page 36: Ischemia-reperfusion injury (IRI)

enzyme scavenger :

2 O‾∙2 +2H+

H2O + O2

H2O2 H2O+ O2

(4) relieve of calcium overload Ca2+ ion blok agent

SOD

CAT

Page 37: Ischemia-reperfusion injury (IRI)

5. CoQ

Inhibit L • (lipid free radical)

2L+ CoQ 2LH+ CoQ

protein enzyme inhibitor:

ulinastatin