Post on 09-Nov-2015
description
Oxidative stress and mitochondrial damage
in sepsis
Helen F. Galley
Oxidative stress and mitochondrial damageSepsis
Most common cause of death on ICU
Mortality rate 20-80% Accounts for up to
50% of ICU deaths Sepsis, severe sepsis,
septic shock, multiple organ failure
Initiated by bacterial products, orchestrated by inflammatory mediators
Complex spectrum of haemodynamic and metabolic derangements
Characterised by uncontrolled inflammatory response
Oxidative stress and mitochondrial damageSepsis
Free radicals are atoms with an unpaired electron
Oxygen derived free radicals produced normally during respiration
Can cause damage but antioxidants limit this damage
Oxidative stress and mitochondrial damageFree radicals
Antioxidants protect against oxidative damage
Endogenous: enzymes -superoxide dismutase, catalase, glutathione system, ubiquinone
Exogenous: vitamins, trace metals, polyphenols, food additives, ubiquinone
Drugs eg propofol
Oxidative stress and mitochondrial damageAntioxidants
Oxidative stress occurs when the balance of radical production outweighs the available antioxidant protection
No oxidative stress
RadicalsAntioxidants
Oxidative stress
Oxidative stress and mitochondrial damageOxidative stress
Radical production Radical damage
Oxidative stress and mitochondrial damageOxidative stress and mitochondria
Sepsis
Oxidative stress
Damage
Organ failure
Oxidative stress and mitochondrial damageSepsis
Protti and Singer. Crit Care 2006; 228:
Oxidative stress and mitochondrial damageSepsis
Mitochondria are a primary source of oxygen derived free radicals
Also a target of oxidative damage leading to mitochondrial dysfunction
Mitochondrial dysfunction may contribute to organ failure in sepsis
Oxidative stress and mitochondrial damageOxidative stress and mitochondria
Low antioxidant levels High levels of markers of
oxidative damage Mitochondrial damage
Oxidative stress and mitochondrial damageOxidative stress in sepsis
45
55
50
60
65
A
n
t
i
o
x
i
d
a
n
t
c
a
p
a
c
i
t
y
%
5 10 151Days after onset of secondary organ failure
Survivors
Non-survivors
Cowley et al. Crit Care Med 1996; 24: 1179-83
Oxidative stress and mitochondrial damageSepsis
Chuang et al. Crit Care 2006; 10: R36
Oxidative stress and mitochondrial damageSepsis
A
n
t
i
o
x
i
d
a
n
t
c
a
p
a
c
i
t
y
5.0
10.0
0
L
i
p
i
d
p
e
r
o
x
i
d
e
m
o
l
/
l
2.5
7.5
ControlsSurvivors
Non-survivors
Galley et al. Crit Care Med 1995; 23: 646-51
Oxidative stress and mitochondrial damageSepsis
15
30
0%
d
e
p
o
l
a
r
i
z
e
d
m
i
t
o
c
h
o
n
d
r
i
a
Adrie et al, Am J Resp Crit Care Med 2001; 164: 389-95
Survivors Non-survivors
Oxidative stress and mitochondrial damageSepsis
Brealey D et al. Lancet 2002; 360: 219-222
Oxidative stress and mitochondrial damageSepsis
Oxidative stress and mitochondrial damageTargeting antioxidants to mitochondria
Oxidative stress and mitochondrial damageTargeting antioxidants to mitochondria
Oxidative stress and mitochondrial damageMitoQ
Rats anaesthetised with isoflurane, tracheostomy, i.v. cannulation
Temperature controlled, ECG, blood pressure
LPS and PepG to mimic sepsis then MitoQ
After 6h measures of organ dysfunction
Oxidative stress and mitochondrial damageMitoQ and sepsis
Lowes et al. Free Rad Biol Med 2008; 45: 1559-65
C
r
e
a
t
i
n
i
n
e
g
/
m
l
250
125
0A
L
T
u
n
i
t
s
/
m
l
1600
1200
800
400
0
ControlsSepsisSepsis +MitoQ
Oxidative stress and mitochondrial damageMitoQ and organ failure
Oxidative stress and mitochondrial damageSummary
Oxidative stress causes mitochondrial damage in sepsis
Mitochondrial damage contributes to multiple organ failure
An antioxidant targeted to protect mitochondria reduce biochemical markers of organ failure in an animal model of sepsis
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