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