Ischemia-Reperfusion injury

Su Chang Fu

90/6/19

Ischemia

• Anesthesiologist: MI, peripheral vascular insufficiency, stroke, and hypovolemic shock

• Restoration of blood flow to an ischemic organ is essential to prevent irreversible cellular injury

• Reperfusion may augment tissue injury

Ischemia-Reperfusion

• Thrombolytic therapy, organ transplantation, coronary angioplasty, aortic cross-clamping, or cardiopulmonary bypass

• Severe: systemic inflammatory response syndrome (SISS) or multiple organ dysfunction syndrome (MODS)

• Account for 30–40% of the mortality in tertiary referral ICU

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

Ischemia at Endothelium

• Express certain proinflammatory gene products(leukocyte adhesion molecules, cytokines) bioactive agents (endothelin, thromboxane A2)

• Repressing other “protective” gene products (constitutive nitric oxide synthase, thrombomodulin) and bioactive agents ( prostacyclin, nitric oxide).

Role of Reactive Oxygen Species

• Including (O2–), (OH–), (HOCl), (H2O2), and nitric o

xide–derived peroxynitrite• Directly damage cellular membranes by lipid peroxi

dation.• Stimulate leukocyte activation and chemotaxis by a

ctivating plasma membrane phospholipase A2 to form arachidonic acid (thromboxane A2 and leukotriene B4)

• Increase leukocyte activation, chemotaxis, and leukocyte–endothelial adherence after I-R

Role of Complement• I/R results in complement activation and the forma

tion of several proinflammatory mediators that alter vascular homeostasis

• C3a, C5a, iC3b, C5b9• Most potent is C5a

• complement may compromise blood flow to an ischemic organ by altering vascular homeostasis and increasing leukocyte–endothelial adherence.

Role of Leukocytes

• I/R results in leukocyte activation, chemotaxis, leukocyte–endothelial cell adhesion, and transmigration– mechanical obstruction– activated leukocytes release toxic ROS, proteas

es, and elastases, resulting in increased microvascular permeability, edema, thrombosis, and parenchymal cell death

Manifestations of I/R injury

• Vascular Injury and the “No Reflow” Phenomenon

• Myocardial Stunning

• Reperfusion Arrhythmias (VT,VF,idioV)

• CNS /GI I/R injury

• Multiorgan Dysfunction Syndrome

• ☆risk factors: hypercholesterolemia, hypertension, or diabetes and so on

Therapeutic Strategies To Prevent I-R Injury

• Ischemic Preconditioning

• Antioxidant Therapy

• Anticomplement Therapy

• Antileukocyte Therapy

Ischemic Preconditioning

• Exposure of tissues to brief periods of ischemia protects them from the harmful effects of prolonged I-R– coronary artery bypass grafting

– reduce liver injury undergoing hepatic resection

• Increases cellular adenosine production and confer protection by augmenting cellular energy stores and/or inhibiting leukocyte adherence

Antioxidant Therapy

• superoxide dismutase, catalase, mannitol, allopurinol, vitamin E, N-acetylcysteine, iron chelating compounds, angiotensin-converting enzyme inhibitors, or calcium channel antagonists– human recombinant superoxide dismutase in pa

tients with hemorrhagic shock– SOD in cadaveric renal transplantation– equivocal

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 inj

ury, blood loss, and cognitive dysfunction in humans undergoing coronary artery bypass graft surgery with cardiopulmonary bypass

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 trans

migration of neutrophils

Therapeutic strategies to attenuate I/R injury

• Controlled, graded reperfusion• Ischemic preconditioning• Aspirin-triggered lipoxin analogs • Antioxidant: SOD, iron chelating compounds, mannitol, allopuri

nol, vitamin E, N-acetylcysteine

• Anticomplement Therapy: anti-C5(h5G1.1-scFv)

• Calcium antagonist• Leukocyte depletion/ Filtration

Conclusion

• Treatment of I-R injury is also confounded by the fact that inhibition of I-R–associated inflammation might disrupt protective physiologic responses or result in immunosuppression.

• timely reperfusion of the ischemic area at risk remains the cornerstone of clinical practice, therapeutic strategies such as ischemic preconditioning, controlled reperfusion, and antioxidant, complement, or neutrophil therapy may significantly prevent or limit I-R injury in humans.

Thanks for your attention!