Ischemia-reperfusion and Acute Apoptotic Cell Death
Ischemia, reperfusion, and apoptosis are vital physiological processes that demonstrate fantastic complexity. These processes have stimulated much interest, and even controversy, in part due to the important role they play in determining cell injury and c
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I Introduction Ischemia, reperfusion, and apoptosis are vital physiological processes that demonstrate fantastic complexity. These processes have stimulated much interest, and even controversy, in part due to the important role they play in determining cell injury and cell death. Both basic scientists and clinicians understand the importance of elucidating these mechanisms. In this chapter, we will discuss the importance of ischemia in human disease, explore the events of reperfusion that may contribute to cell injury following ischemia, review the primary mechanisms of apoptosis, and finally speculate on the mechanisms that link ischemia-reperfusion (I/R) and acute apoptosis.
I Ischemia: Scope of the Problem Ischemic disease, in which blood flow is compromised to a regional vascular bed, whole organ, or globally to the entire organism, is responsible for an enormous degree of morbidity and mortality from such varied conditions as cardiac arrest, cerebrovascular accident, traumatic injury, and myocardial infarction [1]. Ischemia to other organs such as kidney, bowel or liver can also produce severe illness, and can occur as a consequence of clinical situations from septic shock to hypotension during surgery. Numerous clinical observations and laboratory studies support the notion that however deleterious ischemia can be, reperfusion of ischemic tissues may also provoke additional adverse consequences [2-7]. While the treatment of ischemia must eventually reperfuse ischemic tissues, our current techniques for reestablishing blood flow promote a severe inflammatory response as well as production of oxygen free radicals, lipid peroxidation, and accelerated cell death. Recently it has been appreciated that these events are also associated with a marked degree of acute apoptotic cell death, with apoptotic markers appearing far more rapidly (in minutes to hours) than earlier reports of apoptosis where cell death required days to become manifest. The effects of this I/R injury can be experienced beyond the scope of the directly injured tissue. Often, profound I/R results in the systemic inflammatory response syndrome (SIRS) and multi-organ system failure (MOF), a leading cause of death in the intensive care unit (ICU) [8]. Perhaps the most dramatic example of I/R injury is demonstrated by resuscitation from cardiac arrest. Cardiac arrest, which represents global whole body ischemic disease, results in at least 300000 deaths each year in the United States alone
J.-L. Vincent (ed.), Yearbook of Intensive Care and Emergency Medicine 2002 © Springer-Verlag Berlin Heidelberg 2002
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B. S. Abella and L. B. Becker
[9]. Survival from cardiac arrest remains dismal some 40 years after the introduction of cardiac compression and electrical defibrillation, with only 1-11 % of patients surviving until hospital discharge after out-of-hospital cardiac arrest [10, 11]. While initial survival from in-hospital cardiac arrest ranges from 25 to over 50%, subsequent survival until hospital discharge is much lower, from 5-22% [12, l3], su
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