NEUTROPHILS V A KEY COMPONENT OF ISCHEMIA-REPERFUSION INJURY

Ischemia-reperfusion injury (IRI) is a common occurrence following myocardial infarction, transplantation, stroke, and trauma that can lead to multiple organ failure, which remains the foremost cause of death in critically ill patients. Current therapeutic strategies for IRI are mainly palliative, and there is an urgent requirement for a therapeutic that could prevent or reverse tissue damage caused by IRI. Neutrophils are the primary responders following ischemia and reperfusion and represent important components in the protracted inflammatory response and severity associated with IRI. Experimental studies demonstrate neutrophil infiltration at the site of ischemia and show that inducing neutropenia can protect organs from IRI. In this review, we highlight the mechanisms involved in neutrophil recruitment, activation, and adherence and how this contributes to disease severity in IRI. Inhibiting neutrophil mobilization, tissue recruitment, and ultimately neutrophil-associated activation of local and systemic inflammatory responses may have therapeutic potential in the amelioration of local and remote tissue damage following IRI. KEYWORDS—Inflammation, multiple organ failure, migration, cytokines ISCHEMIA-REPERFUSION Clinical setting of ischemia-reperfusion Ischemia-reperfusion (IR) has been recognized as a cause of clinical sequelae for more than half a century (6) and remains a common occurrence in coronary bypass surgery, organ transplantation, gut hypoperfusion, and stroke (7, 8). IR is recognized as a complex cascade of events including interactions between vascular endothelium, interstitial compartments, circulating cells, and numerous biochemical entities that follow ischemia. Inflammation is a key mediator of IR, and aspects of the involvement of the innate immune system have been reviewed by others (8Y10). Despite our knowledge of the pathophysiology of IR, injury caused by IR precedes clinical observation, and once apparent, it is often too late for intervention. Hence, there is still a need for a therapeutic that could prevent or reverse the effects of the injuries caused by IR (7). A number of failed clinical trials demonstrated that intervention during the first seconds of reperfusion is imperative, and thus the window of opportunity during reperfusion is limited. Therefore, therapeutic options need to be fast acting, readily available by clinicians, and not adversely damaging in their own right. Causes and effects of ischemia-reperfusion injury IR is initiated by an ischemic episode, where blood supply is restricted to a portion of an organ or the whole organ, initiating cell death, which is further exacerbated when blood flow is returned. Ischemia results in tissue hypoxia that causes a build-up of metabolic intermediates and reactive oxygen species (ROS), namely, superoxide, hydrogen peroxide, and hydroxyl radicals. Reactive oxygen species increase intracellular calcium, cause pH changes, and concomitantly deplete ATP and nitric oxide (NO), resulting in damage to cell organelles and leading to necrotic cell death (2, 7). Excessive periods of ischemia, ranging from a few minutes to half an hour or more (11Y13), depending on the organ, activates metabolic intermediates and ROS resulting in an overwhelming inflammatory response that leads to ischemia-reperfusion injury (IRI). Increased ROS quenches the production of NO and damages endothelial cells, resulting in loss of barrier integrity and release of ROS into the extracellular matrix (13, 14). This increases expression of adhesion molecules (8); acts as a chemoattractant for neutrophils, initiating their recruitment (14); activates the complement cascade (15, 16); and promotes apoptotic cell death (17, 18). Resident macrophages and damaged endothelial cells release proinflammatroy cytokines, further recruiting, activating, and aiding in migration of neutrophils. This overwhelming inflammatory response can lead to acute respiratory distress syndrome (ARDS) or systemic inflammatory response syndrome (SIRS) that are central to the pathogenesis of multiple organ failure (MOF) (1Y4), which has a mortality rate of 70% (5). IR injury physiology is complex, but the primary response cells to IRI are neutrophils, which infiltrate the damaged tissue within minutes of activation. Several studies in the 1980s and 1990s investigated the role of neutrophils in IRI (19). In the past 2 decades, more emphasis has been given to the role of molecular, rather than cellular, targets such as 463 SHOCK, Vol. 40, No. 6, pp. 463Y470, 2013 Address reprint requests to Matthew Allister Cooper, PhD Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Rd, St Lucia, 4072, Queensland, Australia. E-mail: m.cooper@uq.edu. au. M.A.C. is grateful for the support of a National Health and Medical Research Council Australia Fellowship (AF51105). T.M. W. acknowledges the funding support of the Australian Research Council (Future Fellowship FT110100332). Z.V. S. is grateful to the IMB for a PhD scholarship. This review has been submitted solely to this journal and has not been previously published in any form in another publication of any type. DOI: 10.1097/SHK.0000000000000044 Copyright 2013 by the Shock Society Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited. complement receptors (20), Toll-like receptors (TLRs) (21), ROS (20), and the proinflammatory cytokines such as tumor necrosis factor ! (TNF-! ) (that was subsequently shown not to be involved in IRI) (22). The roles of cytokines, ROS, complement, and TLRs have been emphasized in the pathogenesis of IRI (20, 21) and support, activate, recruit, and amplify the destructive function of neutrophils. Nevertheless, recent studies have returned focus to the role of neutrophils as a key player in the pathophysiology of IRI (16, 23Y25). In this review, we highlight the feedback loop of neutrophil recruitment and excessive damage at the site of IRI and how this can result in MOF.