Pathophysiology of reperfusion injury

Abstract

INTRODUCTION Ischaemia-Reperfusion Injury (IRI) is defined as the paradoxical exacerbation of cellular dysfunction and death, following restoration of blood flow to previously ischaemic tissues. Reestablishment of blood flow is essential to salvage ischaemic tissues. However reperfusion itself paradoxically causes further damage, threatening function and viability of the organ. IRI occurs in a wide range of organs including the heart, lung, kidney, gut, skeletal muscle and brain and may involve not only the ischaemic organ itself but may also induce systemic damage to distant organs, potentially leading to multi-system organ failure. Reperfusion injury is a multi-factorial process resulting in extensive tissue destruction. The aim of this review is to summarise these molecular and cellular mechanisms and thus provide an insight into possible windows for effective therapeutic intervention. ISCHAEMIA ATP and mitochondrial function Ischaemia occurs when the blood supply is less than the demand required for normal function, resulting in deficiencies in oxygen, glucose and other substances required for metabolism. Derangements in metabolic function begin during this ischaemic phase. Initially, glycogen breakdown by mitochondrial anaerobic glycolysis produces two molecules of adenosine triphosphate (ATP) along with lactic acid, resulting in a decrease in tissue pH, which then acts by negative feedback to inhibit further ATP production. (Figure 18.1) ATP is then sequentially broken down into adenosine diphosphate (ADP), adenosine monophosphate (AMP) and inosine monophosphate (IMP) and then further into adenosine, inosine, hypoxanthine and xanthine.