Ischemia Reperfusion Injury

Shahrul I. Ibrahim, Rodney K. Chan, and Herbert B. Hechtman

Department of Surgery, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts

Introduction

Over the years, scientists have been studying the phenomenon of ischemia-reperfusion injury (IR). In simple terms, it is the resultant injury to tissues that are reperfused following a period of ischemia. It can be a localized event or it can be an overwhelming global phenomenon affecting various organs in the body, so-called remote organ injury. This is rather paradoxical, as one would expect the restoration of blood supply to be beneficial, but in effect the injury sustained following reperfusion is far worse than that from the ischemic event alone.

The clinical relevance of reperfusion injury is enormous and encompasses many different disciplines of medicine. Every successful free flap, organ transplant, balloon angio-plasty, or decompression fasciotomy can be threatened by ischemia-reperfusion injury. It is a common clinical problem but there has so far been no effective treatment. Early research implicated oxygen free radicals and neutrophils as central to ischemia-reperfusion injury, but this did not lead to any successful clinical trials, let alone treatment. The Harvard physiologist Walter Bradford Cannon and his colleagues stimulated much of the early research work in ischemia-reperfusion. Cannon proposed the humoral theory of disease, that all bodily functions are controlled by circulating factors [1].

Events Occurring during Ischemia-Reperfusion

Rapid changes occur during ischemia, which leads to pathway changes in signaling and surface molecule expression. There is accumulation of toxic products intracellularly, leading to apoptosis and necrosis. Ischemia can be partially or completely reversible or irreversible, depending on its severity and duration. Following reperfusion, accumulated toxic metabolites are flushed into the general circulation, which may have adverse local or remote effects on organs.

Two major concepts have been forwarded regarding the mechanisms of ischemia-reperfusion injury. Early studies implicated neutrophil stimulation and oxygen free radicals as the main culprits. Following ischemia, there is enhanced neutrophil adherence to endothelial cells secondary to increased expression of adhesion molecules. This then leads to neutrophil diapedesis, their oxidative burst, and the formation of oxygen free radicals [2].

Most recent studies, however, point toward ischemia-reperfusion as part of the inflammatory response to injury, involving the complement system. The fact that numerous studies employing novel ideas of blocking neutrophils or oxygen free radicals failed to produce any meaningful or clinically relevant findings has changed the focus of investigators toward the complement system, which was first described in myocardial infarction in the 1980s.

Overview of Inflammation

Inflammation involves a complex series of reactions including the localized accumulation and activation of leukocytes and certain plasma proteins following a toxin exposure, cell injury, or infection. Inflammation is a protective mechanism, controlling infections and promoting tissue repair; it can also be a cause of tissue damage and disease if prolonged or overly intense.

Proinflammatory cytokines and chemokines are released in response to injury or infection. These activate mast cells in the connective tissue as well as basophils, neutrophils, and platelets. These leukocytes can migrate from injured microvessels and release or stimulate the synthesis of vasodilators such as nitric oxide, histamine, bradykinins, and prostaglandins, as well as some powerful vasoconstrictor agents including leukotrienes and thromboxane A2. Products of the complement system can also trigger mast cell and platelet release of vasoactive agents.

Cytokines are polypeptides produced in response to microbes and other antigens that mediate and regulate immune and inflammatory reactions. They are structurally diverse but share several properties: secretion is a brief, self-limiting event; the actions often are pleiotropic and redundant; they often influence the synthesis and actions of other cytokines; actions may be local or systemic; these actions are initiated by cytokine binding to specific membrane receptors; the expression of cytokine receptors and the resultant cell responsiveness are regulated by external signals; and cellular responses to cytokines are due to changes in gene expression in target cells. Examples of cytokines include the interleukins, tumor necrosis factor (TNF), and the interferons.

Neutrophils play a major role in the immune system and are recruited locally into sites of injury by chemotactic agents including lipopolysaccharide derived from bacterial cell walls, cytokines, eicosanoids produced by local tissue monocytes and endothelial cells, and complement-derived anaphylotoxins C3a and C5a. Once neutrophils accumulate at the target site, they are stimulated by chemoactivators to release oxygen free radicals and proteases whose objective is to destroy offending organisms. In severe injury, infection or ischemia-reperfusion injury, there is indiscriminate and uncontrolled neutrophil-endothelial adhesion and the release of injurious agents that damage host tissues [3].

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Essentials of Human Physiology

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