ischemia-reperfusion injury (iri)
DESCRIPTION
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 PresentationTRANSCRIPT
Ischemia-reperfusion injury (IRI)
Chapter 10
Department of Pathophysiology, Anhui Medical University
Yuxia Zhang
Concepts: IRI, oxygen/calcium/pH paradox
Causes and conditions of IRI
Mechanisms of IRI injury
Metabolic and functional alterations
Prevention and treatment principle
Contents
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
1.Concept
IRI
the reestablishment of blood flow after prolonged ischemia aggravates the tissue damage.
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
Oxygen paradox
Hypoxia liquid perfuse organ or culture without oxygen
injury
restore perfusion severe injury
2. Cause of ischemia-reperfusion injury and affecting factor
Recover from cardiac arrest
Organ transplantation
Lysing thrombi
( 1 ) cause
( 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
Branch circulation : chronic
O2 consumption rate
[K+ ], [Mg2+]condition of reperfusion
T, pressure,pH,Na+,Ca2+
protection
T, pressure,Na+,Ca2+ damage
3. Mechanisms of IRI
• role of oxygen free radical
• calcium overload
• role of leukocyte
(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
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
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·
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
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
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
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
membrane lipid peroxidation
phospholipase Cphospholipase D
PGs , LTsTXA2
damage of mitochondria membrane
ATP
enzymes :
channels:
inhibition of protein function
destruction of nuclear acid
base hydroxylation 、 breakdown of DNA
HEALTHY CELL (left) | FREE RADICAL DAMAGE (right)
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
K+
Na+
3Na+
Ca2+
ATP↓
Na+↑Ca2+↑
Ischemia
mechanism of calcium overload
Reperfusion
Abnormal Na+-Ca2+ exchange
direct activation : intracellular sodium↑
indirect activation ( 1 ): intracellular 【 H+ 】↑
3Na+
Ca2+
Na+
K+
H+
Na+
ReperfusionH+↓
H+↑Na+↑
Ca2+↑
IschemiaH+↑
indirect activation ( 2 ): activation of PKC
ischemia NE α1 – receptor
NE
SR
myofilament
catecholamine β – receptor [Ca2+] i
β Cellular membrane
Ca2+ ↑
L Ca2+- channel
Damage of mitochondria
damage of cellular membrane:
injury of biomembrane
[Ca2+ ] ↑
ATP
Ca 2+ - ATPasecalcium overload
Damage of mitochondria and sarcoplasmic
Damage ofSarcopasmic
Pathogenesis of calcium overload
Damage mitochondria : ATP ↓
promote OFR formation : damege aggravation
Stimulating the phospholipase : injury of
membrane cell and cell organ
mitochondrial dysfunction
(3) role of leukocyte
activation,margination and aggregation of
PMNs after reperfusion
adhesion molecule ;chemotatic factor;mediators of inflammation
Neutrophil activation
ROS Inflammatorymediators
Injury of Micro-vessels
No-reflow phenomenonCell injury
Role of Neutrophil
Reperfusion
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
Heart InjuryHeart Injury
Ischemia-reperfusion injury
Calcium overload Free radical
Destroy of contractile protein
Myocardial stunning
Ca++ K+ Na+
Arrhythmia Cell death
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
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
(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
enzyme scavenger :
2 O‾∙2 +2H+
H2O + O2
H2O2 H2O+ O2
(4) relieve of calcium overload Ca2+ ion blok agent
SOD
CAT
5. CoQ
Inhibit L • (lipid free radical)
2L+ CoQ 2LH+ CoQ
protein enzyme inhibitor:
ulinastatin