REPERFUSION INJURY

SALEH AL MOCHDAR
Definition
What is ischemia-reperfusion injury?

“The restoration of blood flow after transient

ischemia may be associated with further
reversible or irreversible cell damage, which is
called ischemia-reperfusion injury or
reperfusion injury ”
• Restoration of blood flow to an ischemic
organ is essential to prevent irreversible
cellular injury

but
• Reperfusion may augment tissue injury
In the definition of ischemia-reperfusion injury
Etiology

Etiology of ischemia-reperfusion injury

Ischemia followed by reperfusion

 Which

factors are involved in reperfusion injury ?

1. Duration of ischemia the longer period of ischemia,
the more severe injury
2. Severity of ischemia the more grievous ischemia,
the more severe injury
3. Speed of reperfusion the faster reperfusion of
blood, the more severe injury
4. Ischemia preconditioning increasing tolerance to
reperfusion injury
Pathophysiology

Why are
more severe injury induced by reestablishment
of blood flow after ischemia?
Vaso-endothelial edema
ATP depletion  decreased Na+- K+ pump function 
Na+ and water  entering cell  endorthelial edema

Vaso-endothelial damage
WBC adherence  OFR increase and NO decrease
Microvascular obstruction
Interstitial edema  Adherence, Aggregation and
Activation of WBC
Alterations of metabolism and
function during ischemia-
reperfusion injury
1. Alterations of brain metabolism
( energy↓, acidosis, FFA ), cAMP↑ / cGMP↓ → PL↑
2. Abnormal electroencephalogram (EEG)
(slow wave, excitatory transmitters  , inhibitory
transmitters ↑)
3. Alterations in brain structure
(edema, necrosis)
OFR Calcium Overload WBC

Damaged endothelium

Vascular Sticking WBC Liable to form

permeability↑ platelets to endothelium thrombosis

Edema Releasing OFR Blocking blood

proteolytic enzymes flow

Aggravating injury
Pathogenesis of ischaemic brain injury

• Depolarization
• Biochemical cascade
• Reperfusion injury
 Excess oxygen Neutrophil
Free radicals infiltration
↓ ↓

ISCHEMIA—REPERFUSION INJURY

↑ ↑

Microvascular damage Calcium overload

Major mechanisms of ischemia- reperfusion injury
Excess Oxygen Neutrophil Microvascular Calcium
Free radicals infiltration damage overload
↓ ↓ ↓ ↓

ISCHEMIA — REPERFUSION INJURY

↓ ↓ ↓ ↓
Heart Brain Liver Intestine
↓ ↓ ↓ ↓
Shock Cytotoxic Jaundice Mucosal
Pump failure edema enlargement necrosis
Arrhythmia Neuron GTP ↑ Ulceration
death Hemorrhage
Pathophysiological basis of prevention and
treatment for ischemia-reperfusion injury
 Cellular change during Ischemia
• Altered membrane potential
• Altered ion distribution (++ intracellular Ca/Na)
• Cellular swelling
• Cytoskeletal disorgnization
• Increased hypoxanthine
• Decreased ATP
• Decreased phosphocreatinine
• Cellular acidosis
 Cellular Effects of Ischemia
• Decreased ATP
• Intracellular accumulation of hypoxanthine
• Toxic reactive oxygen species (ROS) during
reperfusion
How to prevent and treat
ISCHEMIA—REPERFUSION INJURY ?
Relieving ischemic condition as a prerequisite
Excess Oxygen Calcium Neutrophil
Free radicals overload infiltration
↓ ↓ ↓
ISCHEMIA-REPERFUSION INJURY
↑ ↑ ↑
OFR Calcium WBC
Scavenger Antagonist Antiboby
Therapy
Therapeutic Strategies To Prevent I-R Injury

• 1. Ischemic Preconditioning
• 2. Antioxidant Therapy
• 3. Anticomplement Therapy
• 4. Antileukocyte Therapy
1. Ischemic Preconditioning

• Exposure of tissues to brief periods of

ischemia protects them from the harmful
effects of prolonged I-R
• Increases cellular adenosine production and
confer protection by augmenting cellular
energy stores and/or inhibiting leukocyte
adherence
2. Antioxidant Therapy
• superoxide dismutase (SOD), catalase,
mannitol, allopurinol, vitamin E, N-
acetylcysteine, iron chelating compounds,
angiotensin-converting enzyme inhibitors, or
calcium channel antagonists
– human recombinant superoxide dismutase in
patients with hemorrhagic shock
– SOD in cadaveric renal transplantation
3. Anticomplement Therapy

• C3 convertase inhibitor
• Soluble complement receptor 1 decrease infarct size by
44% in a rat model of myocardial I-R.

• “Humanized,” recombinant, single-chain

antibody specific for human C5 (h5G1.1-
scFv) significantly attenuate complement activation, leukocyte activation,
myocardial injury, blood loss, and cognitive dysfunction in humans undergoing coronary
artery bypass graft surgery with cardiopulmonary bypass
4. Antileukocyte Therapy
• inhibition of inflammatory mediator release or
receptor engagement, leukocyte adhesion
molecule synthesis, or leukocyte–endothelial
adhesion
– Leukocyte depletion/ Filtration
– Soluble interleukin-1 receptor antagonists, anti–tumor necrosis
factor antibodies, or platelet activation factor–leukotriene B4
antagonists
– Aspirin-triggered lipoxins prevent chemotaxis, adhesion, and
transmigration of neutrophils
Therapeutic strategies to attenuate I/R injury
• Controlled, graded reperfusion
• Ischemic preconditioning
• Aspirin-triggered lipoxin analogs
• Antioxidant: SOD, iron chelating compounds,
mannitol, allopurinol, vitamin E, N-acetylcysteine
• Anticomplement Therapy: anti-C5(h5G1.1-scFv)
• Calcium antagonist
• Leukocyte Filtration
Conclusion
• Timely reperfusion of the ischemic area at risk remains
the cornerstone of clinical practice, therapeutic strategies
such as
ischemic preconditioning,
controlled reperfusion,
antioxidant,
complement, and / or neutrophil therapy
may significantly prevent or limit I-R injury in humans.
Thank you