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Oxidative stress and

mitochondrial damage
in sepsis
Helen F. Galley

Oxidative stress and mitochondrial damage


Sepsis

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

Oxidative stress and mitochondrial damage


Sepsis

Initiated by bacterial

products, orchestrated by
inflammatory mediators

Complex spectrum of

haemodynamic and
metabolic derangements

Characterised by

uncontrolled inflammatory
response

Oxidative stress and mitochondrial damage


Free radicals

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 damage


Antioxidants

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 damage


Oxidative stress
Oxidative stress Oxidative stress
occurs when the
balance of radical
production
Radicals
outweighs the
available
antioxidant
protection

No oxidative stress

Antioxidants

Oxidative stress and mitochondrial damage


Oxidative stress and mitochondria

Radical production

Radical damage

Oxidative stress and mitochondrial damage


Sepsis
Sepsis

Oxidative stress
Damage
Organ failure

Oxidative stress and mitochondrial damage


Sepsis

Protti and Singer. Crit Care 2006; 228:

Oxidative stress and mitochondrial damage


Oxidative stress and mitochondria

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 damage


Oxidative stress in sepsis

Low antioxidant levels


High levels of markers of
oxidative damage

Mitochondrial damage

Antioxidant capacity %

Oxidative stress and mitochondrial damage


Sepsis
65
Survivors
60
55
50

Non-survivors

45
1
5
10
15
Days after onset of secondary organ failure

Cowley et al. Crit Care Med 1996; 24: 1179-83

Antioxidant capacity

Oxidative stress and mitochondrial damage


Sepsis

Chuang et al. Crit Care 2006; 10: R36

Oxidative stress and mitochondrial damage


Sepsis

Lipid peroxide mol/l

10.0
7.5
5.0
2.5
0

Galley et al. Crit Care Med 1995; 23: 646-51

Controls
Survivors
Non-survivors

% depolarized mitochondria

Oxidative stress and mitochondrial damage


Sepsis
30

15

0
Survivors

Non-survivors

Adrie et al, Am J Resp Crit Care Med 2001; 164: 389-95

Oxidative stress and mitochondrial damage


Sepsis

Brealey D et al. Lancet 2002; 360: 219-222

Oxidative stress and mitochondrial damage


Targeting antioxidants to mitochondria

Oxidative stress and mitochondrial damage


Targeting antioxidants to mitochondria

Oxidative stress and mitochondrial damage


MitoQ

Oxidative stress and mitochondrial damage


MitoQ and sepsis

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 damage


MitoQ and organ failure
1600
1200

ALT units/ml

Creatinine g/ml

250

125

800
400
0

Controls
Sepsis
Sepsis +MitoQ
Lowes et al. Free Rad Biol Med 2008; 45: 1559-65

Oxidative stress and mitochondrial damage


Summary

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