Download 没有幻灯片标题

Ischemia-reperfusion
injury (IRI)
Introduction
1955, Sewel
tied up coronary of dog， loose suddenly
ventricular fibrillation
。
Kane
tied up left entricular branch of coronary
of rat
ECG no obvious change
relieve deligation
arrhythmic
1972
1978
1981
Flore
Modry
Greenberg
kidney IRI
lung IRI
intestine IRI
Concept:
based on ischemia injury of tissue and organs
restoration of blood flow after transient or
ischemia
further reversible or irreversible cell damage
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
abnormal，
calcium paradox
Oxygen paradox
Hypoxia liquid perfuse organ or culture
without oxygen
injury
restore perfusion
severe injury
Ⅰ. Cause of ischemia-reperfusion injur
y and affecting factor
1. cause
coronary in spasm
antispasmotic
thrombosis
thrombolytic therapy
coronary by-pass
operation on heart: no-reflow
organ transplant
2．Affecting factor
⑴ ischemic
time
small
animals
5-10min: arrhythmia
20-30min: ventricular
tremor
big
20-40min: reversible injury
animals 40-60min: irreversible
injury
diversity between small and big animal
Changes of ischemic perfuse: ATP、Ca2+、K+
⑵ collateral(侧枝) circulation：chronic
⑶ O2 consumption rate
[K+ ] , [Mg2+]
protection
[Na+ ] , [Ca2+]
damage
⑷ electrolytes
(5) condition of T, pressure,pH,Na+,Ca2+
reperfusion T, pressure,Na+,Ca2+
protection
damage
Ⅱ. pathogenesis of ischemia-reperfusion
injury
1. The role of free radical
⑴ kinds and concept of free radical
free radical:
normal: O2 +4e+4H+
2H2O
- + 2H +
-+H +
-+H +
e
e
e
O2 → O •2
H2O2
OH •
H 2O
e-
H2O
oxygen free radical:
O •2 、OH •
kinds of
(active oxygen: 1O2、H2O2
free radical
OH • )
lipid free radical:
L•、LO•、LOO•
others: Cl•、CH3•、NO
(2) mechanism of increase of oxygen free radical
① formation of oxygen free radical
nature oxidation of Hb , Cyt C
O2
O ‾∙2
O ‾∙2
H2O2
OH∙
H2O
H2 O
oxidation of enzyme : xanthine oxidase(XO)
xanthine
uric acid
O2 O ‾∙2
Mitochondria: O ‾∙2
normal: O2+4e+4H+→H2O+ATP
abnormal :O2+e→ O·-2 +e +2H+→H202+e+H+→
OH· +e+H+→H20
Cyt P450
O insert
O +2 H
+
C—H
C—OH
H2O
O ‾∙2 H2O2
Produce of OH·
SOD
O·-2+ O·-2+2H+
H2O2+O2
O·-2+H2O2
Fenton Haber-Weiss：
SOD
O·-2
Fe2+
H2O2
OH· + OH·+O2
Fe3+
OH· + OH-
（2） lipid free radical
concept：
types：L· , LO·
LOO·
（3）non- lipid free radical:
NO· 、 ONOO-
They are balance between produce and clearance
Haber-Weiss reaction(Fenton reaction )
OH ∙
1O
2
Fe3+ + O‾∙2
Fe2+ + O2
H2O2
Fe3+ + OH- + OH∙
O ‾∙2 + H2O2 Fe盐 O2 + OH-+ OH∙
1O + OHO‾∙2 + OH∙
2
CI+ + H2O
H2O + OCl1O + Cl- + H O
OCl+ H2O2
2
2
photosensitive substance
O2
1O
2
effects:WBC
2O‾∙2 + 2H +
H2O2
SOD
H2O2+ O2
O2
Other oxidase
2H+
H2O2
application
disinfection
② increase of oxygen free
XD
Xanthine oxidase (XO) :
Ischemia
ATP
xanthine
dehydrogenase
[Ca2+]i
xanthine
oxidase
Xanthine oxidase pathway
ischemia reperfusion
ATP
ADP
AMP
XD 2+
Adenine nucleoside
Ca
Hypoxanthine nucleoside xo
Hypoxanthine
xanthine+O‾∙2 +H2O
O2
XO
Uricacid +O‾∙2 +H2O
Fe 2+
OH∙
The effects of leucocyte
reperfusion：oxygen consumption of infiltrated WBC
↑70-90% O2
NADPH氧化酶
NADPH +2O2
NADH+O2+2H+
2O·-2 +NADP++H+
NADH氧化酶
H2O2+NAD+ +H+
Phenomenon of increase in production of
oxygen radicals
1.repiratory burst
(oxygen burst)
2.hypoxia
O‾∙2 \ OH∙
mitochondria repiratory chain
Ca2+
O‾∙2
(3) damage action of free radical
① membrane lipid peroxidation
cellular membrane permeability
lipid peroxidation of membrane
[Ca2+] i
calcium overload
lipid cross-linked
inhibition of Na+-pump
and Ca2+-pump
calcium overload
[Na+] i , [Ca2+] i
membrane lipid
phospholipase C
peroxidation
phospholipase D
damage of mitochondria membrane
PGs , LTs（花）
TXA2
ATP
② inhibition of protein function
enzymes ：stop heart beat IR GSH(blood)
of protein
channels:
③ destruction of nuclear acid
DNA- DNA, DNA-protein :
injury
(1) mechanism of calcium overload
Ca2+ input
① abnormal exchange of Na+/Ca2+
ATP
Na+-pump
[Na+] i
exchange of Na+(out)/Ca2+
hypoxia exchange
acidosis of Na+(in)/H+(out)
[Na+] i
normal exchange of Na+(in)/Ca2+(out) ，
(in) (convert)
ischemia
α1 – receptor
Ca2+
catecholamine
H+
α1
Na+
IP3 and DG
PKC
S R
2+
Ca
Normal:βreceptor
Ca2+
Ca2+
catecholamine
β – receptor
[Ca2+] i
L Ca2+- channel
β
Cellular membrane
Ca2+
pre-apply anti-Ca2+ drugs GOOD
② injury of biomembrane
damage of cellular membrane
normal
Ca2+ bridge
glycocalyx
Cellular membrane
Cellular membrane
No Ca2+
glycocalyx
Cellular membrane
reperfusion Ca2+
glycocalyx
Cellular membrane
Ca2+
lipid break up
PLA2
Damage of mitochondria and sarcoplasmic
Damage of
mitochondria
Damage of
Sarcopasmic
ATP
Ca2+- ATPase
calcium
overload
(2) Damage mechanism of calcium overload
①phospholipase
injury of cell membrane
and cell organ
②output of Ca2+
consumption of ATP
③Ca2+ + phosphate
production of ATP
deposition
④ [Ca2+] i
⑤ [Ca2+] i
XO
free radical
3. role of leukocyte
In 1984 ， Mullane found that conorary was
obstructed 60min，
Engler， Ischemia
phospholipase
LTs
Congregate of leukocyte
Expression of adhesion molecule
Release inflammatory factor
Production of free radical
no-reflow
5. Role of neutrophil :
1) Injury of microvessle
microcirculation：
caliber contracte , dialate
permability
2) Injury of cells
Ⅲ. Changes of function and metabolism
1. changes of heart in ischemia-reperfusion injury
arrhythmia
heart function
cardiac output
free radical
energy
calcium overload
reperfusion
myocardial
structural
damage
damage of mitochondria
sweep of ADP，AMP
produce ATP
destruction of membrane
rupture and dissolve of myofibril
damage of mitochondrion
2. changes of brain in
ischemia-reperfusion injury
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
3. Others
Colone, kidney
Ⅳ. 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
VitC:
FR (lipid)
FR
clear OH∙
β-cartenoids: clear
GSH
(water)
1O
2
（2）enzyme scavenger：
2 O‾∙2 +2H+
SOD
CAT
H2O + O2
H2O2
H2O+ O2
4. relieve of calcium overload
Ca2+ ion blok agent
5. CoQ
Inhibit L • (lipid free radical)
2L+ CoQ
2LH+ CoQ
protein enzyme inhibitor:
ulinastatin