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Ischemia and Reperfusion Injury: When Cells Almost Die

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Ischemia and Reperfusion Injury: When Cells Almost Die Peer Reviewed CE Article #1 Ischemia and Reperfusion Injury: When Cells Almost Die Amy N. Breton, CVT, VTS (ECC) Veterinary Emergency and Specialty Center of New England Waltham, Massachusetts schemia is defined as inadequate blood supply to a part ing energy for metabolism within cells.3 One of the fastest of the body, usually caused by partial or total block- ways that ATP is produced is by oxidative phosphorylation, age of an artery. Reperfusion injury occurs when tissue which, as the name implies, requires oxygen.3 Despite the I 3 perfusion and oxygenation are restored to an area that has importance of ATP, cells do not stockpile ATP. They only been affected by an ischemic event. make what they need for a particular time. When ischemia Ischemia/reperfusion (I/R) injury is a complex cascade occurs, oxygenation of cells ceases, resulting in anaerobic of events resulting in devastating effects on the body, ATP production, which is less efficient.3 sometimes including death. Despite more than 70 years of When oxygen becomes unavailable, cells begin anaero- research, I/R injury is not fully understood. Events such as bic glycolysis. This process can be a lifesaving way for cells gastric dilatation–volvulus (GDV), mesenteric torsion, or to obtain energy; however, it is extremely wasteful. During strangulation of a limb can lead to I/R injury. It is important anaerobic glycolysis, pyruvic acid and hydrogen atoms for all veterinary personnel to understand I/R injury so that combine with nicotinamide adenine dinucleotide (NAD) treatment and prevention can begin as early as possible. to form NADH and H+.3 If the buildup of NADH and H+ within cells becomes too great, the anaerobic process stops, The Ischemic Cascade terminating energy production.3 However, NADH and H+ The chain of events involved in I/R injury can be broken combine to form lactic acid, which diffuses from cells rap- down into the ischemic cascade (BOX 1) and reperfusion idly so that the process can continue.3 Although this is not injury (BOX 2). An ischemic episode involves a series of ideal, the body can safely continue anaerobic glycolysis for events called the ischemic cascade. Within 5 minutes of the several minutes. If the process continues for too long, as development of ischemia, the electrolyte balance within in ischemia, lactic acid can build up (lactic acidosis), indi- cells becomes disturbed.1 The ischemic cascade usually cating worsening illness. As a consequence of lactic acido- continues for 2 or 3 hours but can last for days, even after sis, pH decreases, injuring and inactivating mitochondria. perfusion is restored to the affected area.2 Although the These mitochondria then break down, releasing toxins that term cascade suggests that events always follow a sequential cause apoptosis. Some researchers think that lactic acid pattern, in the ischemic cascade, events can occur linearly may also interfere with the recovery of aerobic ATP pro- or simultaneously.1 duction after ischemia.3 A lactate level should be obtained To fully understand the ischemic cascade, it is important for all ischemic patients. Values <2 mmol/L are normal. In to understand the role of adenosine triphosphate (ATP) in patients with GDV, a level >6 mmol/L is associated with the body. ATP is a multifunctional nucleotide (a structural increased gastric necrosis. In 1999, a study of 102 dogs component of DNA and RNA) that is considered to be with GDV found that 58% of dogs with a blood lactate level the most important nucleotide responsible for transport- >6 mmol/L survived, whereas 99% of dogs with a level <6 Vetlearn.com Veterinary Technician | JULY 2010 E1 ©Copyright 2010 MediMedia Animal Health. This document is for internal purposes only. Reprinting or posting on an external website without written permission from MMAH is a violation of copyright laws. CE Article #1 BOX 1 by neutrophils.7 Even after reperfusion, the redistribu- tion of blood to affected areas may not produce enough The Ischemic Cascade1,5–9,12 force to clear clogs.7 The full pathway of NFκB is still not • Lack of oxygen causes failure of the normal aerobic understood.1 process for making ATP. • Cells switch to anaerobic respiration, creating lactic Reperfusion Injury acid. It would seem that simply reintroducing oxygen into an • Potassium leaks from cells, while sodium and calcium ischemic area would be beneficial. In patients with GDV, enter cells. oxygen is restored when the stomach is decompressed or • Calcium converts XDH to XO. untwisted, allowing oxygen and blood to flow back into the stomach wall. However, the reintroduction of oxygen • XO builds up. into affected areas initiates a complex chain of events. The • NFκB is activated, activating inflammatory mediators harsh effects of ischemia alone do not cause nearly as much and platelet-activating factor. damage as reperfusion does.1 The longer the duration of • Damaging free radicals are formed. the ischemic event, the greater the insult from reperfusion injury.1 An ischemic event may not be long enough to pro- • Mitochondria break down and start apoptosis. duce a reperfusion injury. • Neutrophils start to overwhelm the affected areas. One of the first events in reperfusion is that oxygen binds • Cells die. with XO that has built up during ischemia. The combina- tion of XO, oxygen, and hypoxanthine forms superoxide - 5 (O2 ), a radical. Superoxide is not that damaging but can mmol/L survived.4 Death is an ischemic event because it inactivate iron–sulfur–containing enzymes, liberating free causes oxygen deprivation at the tissue level. Lactic acid iron and generating highly reactive hydroxyl (-OH) radi- buildup is the major cause of rigor mortis.3 cals. Hydroxyl is considered to be a reactive oxygen species When ATP fails to form, cells become depolarized, (ROS). allowing calcium and sodium (normal extracellular electro- An ROS is an oxygen-containing molecule that is very lytes) to enter cells.5 Potassium, which is normally found in chemically reactive. ROS molecules react quickly with cells, leaks rapidly into the extracellular space.5 Excessive other molecules. If present in high levels, they can damage intracellular calcium overexcites cells, creating free radi- cellular macromolecules such as DNA and RNA or cause cals and many enzymes, such as xanthine dehydrogenase endothelial injury, microvascular dysfunction, and apopto- (XDH) and xanthine oxidase (XO). The extent of ischemic sis.8 ROS molecules can form within 10 to 30 seconds after damage is related to the amount of calcium that enters cells the onset of reperfusion.5 and the duration for which the intracellular calcium level During ischemia, neutrophils leak into the endothelium remains elevated.6 The longer calcium stays in cells, the because of the activation of NFκB and XO. The inflam- more harmful compounds it can create. matory response to reperfusion accelerates the influx of One of the most important events involving calcium is neutrophils to the affected area.9 Neutrophil activation the conversion of XDH to XO.4 XO requires oxygen for alone can lead to even more ROS formation.5 The inflam- activation. During ischemia, oxygen is not present, so XO matory cascade accelerates during reperfusion. In short, accumulates without getting used. Later, during reperfu- neutrophils and macrophages attack reperfused tissues. sion, XO can damage cells. Inflammatory cytokines are released as neutrophils are Another important event during ischemia is the activa- activated.1 When the body becomes overwhelmed with tion of nuclear factor–κB (NFκB), leading to the produc- inflammatory cells, cytokines can be overproduced, result- tion of inflammatory mediators.1 NFκB becomes activated ing in massive cytokine influx (hypercytokinemia) into the during stress.3 NFκB activates inflammatory cytokines and affected tissue.1 The exact mechanism behind this phenom- their receptors as well as platelet-activating factor.1 This enon is not fully understood.1 allows neutrophils to pass through the vascular endothe- lium. Activated neutrophils are generally rigid because of Complications hypoxia and acidosis, which accompany ischemia. Because The ischemic insult sets up the body for a damaging chain of the alteration of the cell membrane and the high number of events that is initiated by reperfusion. Although some of neutrophils, capillaries may become plugged or clogged researchers debate the exact relationship between I/R injury E2 JULY 2010 | Veterinary Technician Vetlearn.com Peer Reviewed and these events, the end result can be the death of the BOX 2 patient. Reperfusion Injury1,5–9,12 Disseminated Intravascular Coagulation • Oxygen is reintroduced into the affected area. In patients with I/R injury, damaged endothelial cells release • XO forms superoxide radicals. substances that activate the clotting cascade. Eventually, the • Superoxide liberates free iron, causing creation of balance between clotting and bleeding becomes disturbed, hydroxyl ROS. resulting in disseminated intravascular coagulation (DIC). DIC is a pathologic process in which blood coagulates • ROS damage macromolecules (i.e., DNA, RNA) and cause endothelial injury, microvascular dysfunction, throughout the body. The result is depletion of platelets and apoptosis. and coagulation factors, creating a risk for increased bleed- ing.1 Petechiae, ecchymoses, and excessive bleeding are • Neutrophils overwhelm the affected areas. often noted in patients with DIC. DIC is generally triggered • The inflammatory process accelerates. when there is a major
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