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

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x

i

d

a

n

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c

a

p

a

c

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y

5.0

10.0

0

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x

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d

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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

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p

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l

a

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c

h

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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

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250

125

0A

L

T

u

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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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