The Role of Pre- and Postconditioning to Avoid the Ischemia-reperfusion Injury Caused by Pneumoperitoneum

Abstract

Any form of trauma, including surgery, is known to result in oxidative stress. Increased intra-abdominal pressure during pneumoperitoneum and inflation-deflation may cause ischemia reperfusion and, so, oxidative stress may be greater during laparoscopic surgery. During an ischaemic period the duration of ischemia could also be serious, thus after reconstruction we always have to face with reperfusion injury. The aim to reduce the reperfusion injury associated pathways has real clinical importance in laparoscopic surgery. The pathogenesis of reperfusion injury is a complex process involving numerous mechanisms exerted in the intracellular and extracellular environment. Reperfusion injury is an obligatory response to the restoration of blood flow after ischemia and is initiated at the very early moments of reperfusion, lasting potentially for days. The extent of the oxidative stress and the consecutive generalized inflammatory response depend on the ischemic-time, the ischemic tissue volume, and the general state of the endothelium leukocyte-tissue functional complex. Ischemia/reperfusion (I/R) can induce various forms of cell death, such as programmed cell death, apoptosis, oncosis and necrosis. Free radical formation is increased during abdominal surgery as a result of ischemia-reperfusion, leukocyte activation, and mitochondrial dysfunction. Apoptosis can be caused by both prolonged ischemia/hypoxia and by reperfusion as well. The mechanisms of reperfusion-induced cell death are not completely understood, but it seems that the occurrence of oxidative stress related to the generation of ROS (Reactive Oxygen Species) may play an important role. ROS has downstream effects, that results in the initiation of a highly orchestrated acute inflammatory response through the release of cytokines, activation of vascular endothelial cells and leukocytes with expression of cell surface adhesion molecules, and up-regulation of a program of pro-inflammatory genes, that contribute to the onset and maintenance of post-ischemic inflammation. Free radicals are highly reactive molecules with unpaired electrons, which are continuously produced in the body by mitochondria, leucocytes, and xanthine oxidase. They have important biological functions such as redox signaling and antibacterial defense. However, they can also react with proteins, lipid membranes, DNA (Deoxyribonucleic acid) and cause damage. The human body is endowed with a complex system of enzymatic and non-enzymatic antioxidants to counteract these adverse effects of free radicals. Oxidative stress occurs when there is an imbalance between the production of free radicals and antioxidant levels. Oxidative stress can be quantified by measuring different biomarkers. This can be done by direct measurement of free radicals, the end-products of free radical damage, or the levels of individual and total antioxidants. Different biomarkers have been used in various clinical settings, and there is not a single biomarker that can truly represent oxidative stress. The phenomenon of ischemic preconditioning has been recognized as one of the most potent mechanisms to protect against myocardial ischemic injury. In experimental animals and humans, a brief period of ischemia has been shown to protect the heart from more prolonged episodes of ischemia, reducing infarct size, attenuating the incidence, and severity of reperfusion-induced arrhythmias, and preventing endothelial cell dysfunction. Although the exact mechanism of ischemic preconditioning remains obscure, several reports indicate that this phenomenon may be a form of receptor-mediated cardiac protection and that the underlying intracellular signal transduction pathways involve activation of a number of protein kinases, including protein kinase C, and mitochondrial KATP channels. Among others, oxidant stress can modify some of the cellular activities that have been implicated in vivo as mediators of the IPC phenomenon. It could thus be hypothesized that reperfusion after the initial, “preconditioning” ischemic episode results in the generation of relatively low amounts of oxygen radicals, insufficient to cause cell necrosis, but enough to modify cellular activities and thus induce IPC. Ischemic PC was first identified in 1986 by Murry et al. This group exposed anesthetized open-chest dogs to four periods of 5 minute coronary artery occlusions followed by a 5-minute period of reperfusion before the onset of a 40-minute sustained occlusion of the coronary artery. The control animals had no such period of “ischemic preconditioning” and had much larger infarct sizes compared with the dogs that did. Aksöyek et. al described that preconditioning can reduce ischemic damage in abdominal organs as well. While relatively easy to implement in a controlled, surgical setting such as transplantation or cardiac surgery, ischemic preconditioning (IPC) is not well-suited to emergency settings, as the onset of myocardial or brain infarction cannot be anticipated. Short periods of ischemia performed just at the time of reperfusion can reduce the infarct size. IPoC was first described by Vinten-Johansen’s group. IPoC can be obtained by different protocols in terms of duration of the periods of reperfusion and ischemia and/or in terms of number of cycles of I/R applied after a sustained ischemia. Virtually in all of the species in which different IPoC algorithms have been tested the proved to be protective, including humans. Taken together both IPC and IPoC activate the same key pathways, that include phosphatidylinositol 3-kinase-Akt and extracellular signal–regulated kinase (ERK/p42-44). IPC and IPoC influence a variety of endogenous mechanisms that operate at numerous levels and target a broad range of pathological mechanisms.