Current Pharmaceutical Design - Volume 12, Issue 23, 2006

We are delighted to introduce this Special Issue of Current Pharmaceutical Design. This collection of review articles from leading international experts in the field explores the main aspects of pharmacological modulation of liver ischemia-reperfusion injury (IRI) and confirms this Journal's commitment to publication of high-quality reviews at the interface between life sciences and clinical application. IRI is a phenomenon whereby the perfusion of a previously ischemic tissue or organ, paradoxically leads to further injury [1]. The local tissue injury is associated with a systemic response resulting in remote organ dysfunction. It is a major factor influencing the outcome of a wide variety of human disease processes including cerebro-vascular events (stroke), myocardial infarction, coronary artery bypass surgery, organ transplantation, liver resection, hemorrhagic shock with fluid resuscitation, limb revascularization and laparoscopic surgery. In the field of liver transplantation ischemia-reperfusion (IR) can lead to graft dysfunction or primary non function. These are associated with a high morbidity and mortality. IR also predisposes to graft rejection. The effect of IRI is particularly evident where liver resection or transplantation is being carried out using steatotic livers. Hepatic steatosis is associated with an impaired microcirculation, poor graft function and increased postoperative morbidity and mortality [2, 3]. The pathophysiology is complex involving many biochemical pathways, some of which have yet to be fully elucidated [4, 5]. Two distinct phases of liver reperfusion injury [5,6,7] have been recognized. During the two hour period of the early phase liver Kupffer cells become activated leading to formation of extracellular reactive oxygen species (ROS) and production of cytokines. ROS and cytokines have a direct cytotoxic effect on endothelial cells and hepatocytes, but they also induce the expression of adhesion molecules and recruitment of neutrophils. These activated neutrophils release ROS and proteases which are responsible for the induced oxidative stress during the late phase (3-48 hours post-reperfusion). Also inducible nitric oxide synthase (iNOS) is expressed resulting in formation of high concentrations of nitric oxide (NO). NO can react with superoxide (O2.-) to yield toxic reactive nitrogen species (RNS) such as peroxynitrite (ONOO-). The injury during the late phase is much more severe compared with that during the early phase. Understanding the mechanisms of liver IR allows therapeutic strategies to be developed. The current strategies are either mechanical (e.g. ischemic preconditioning or remote preconditioning) or pharmacological. Ischemic preconditioning is the application of short periods of ischemia and reperfusion to an organ prior to prolonged ischemia whereas in remote preconditioning cycles of brief ischemia are applied to a remote organ (e.g. lower limb) prior to prolonged ischemia of the target organ (e.g. liver, heart). Preliminary studies with both techniques have shown a reduction in liver IRI although further studies and refinement of technique are required [8-10]. Mechanical methods of reducing IRI are worthwhile but are limited in their application whereas pharmacological modulation may have universal application. The challenge to scientists and clinicians is to gain a better understanding of the basic mechanisms of IR, to develop new targets and drugs therapies and then to translate this to improved outcomes in clinical practice. This special issue brings together international experts in the field of IR pathophysiology to review the main mechanisms and the pharmacological approaches which can be used to ameliorate liver IRI. Hepatic IR results in an inflammatory cascade involving pro inflammatory cytokines which initiate leukocyte recruitment. However there are also endogenous mechanisms for limiting the inflammatory response which include anti-inflammatory cytokines. Husted et al. [11] focus on this pro and anti-inflammatory cytokine balance and how this might be manipulated for therapeutic benefit. One of the main consequences of an uncontrolled inflammatory response in IR is the formation of ROS and RNS. As with the pro and anti inflammatory cytokines a balance exists. At low concentration they help the body respond to injury acting as messengers in signal transduction pathways. When produced in large amounts they overwhelm the endogenous antioxidant system resulting in tissue injury from oxidative stress [12]. Galaris et al. [13] describe the source and mechanism of ROS generation in liver IR, how they result in tissue injury and review current strategies for combating oxidative stress. The important role of free ferrous iron in hydrogen peroxide (H2O2)-mediated toxicity is highlighted and the rationale of combining antioxidants with iron chelating agents......

Hepatic ischemia/reperfusion injury is a complication of liver resection surgery, transplantation and hypovolemic shock, leading to local and remote cellular damage and organ dysfunction. This injury is largely a result of an acute inflammatory response characterized by the induction of a cascade of proinflammatory mediators that culminates in the recruitment of leukocytes to the post-ischemic tissue leading to parenchymal cell injury. Endogenous regulatory mechanisms exist to attempt to control this inflammatory response. These include anti-inflammatory cytokines that function to suppress proinflammatory mediator expression. In this review, we address the current knowledge of the pro- and anti-inflammatory cytokine components of the acute liver inflammatory response to ischemia/reperfusion as well as how these cytokines can be manipulated to reduce post-ischemic liver injury.

Ischemia-reperfusion (IR) injury is a multifactorial process triggered when the liver or other organs are transiently subjected to reduced blood supply followed by reperfusion. It has been shown that "reactive oxygen species" (ROS) are generated during ischemia and reperfusion and may represent pivotal mediators of the ensuing pathological complications. In some cases, however, moderate production of ROS may exert protective effects, a phenomenon presumably related to "ischemic preconditioning". This review will focus mainly on: a) describing the sources and the biochemical mechanisms of ROS generation during ischemia and reperfusion, b) discussing current developments in understanding the biochemical pathways by which ROS may induce toxic or protective effects, c) critically evaluating the results of previous attempts to counteract the toxic effects of ROS by using a variety of antioxidant and transition metalchelating agents, and d) if feasible, proposing potential new pharmaceutical agents aimed at ameliorating ROS-inducing deleterious effects during reperfusion. It is concluded that ROS are generated from different sources, at different periods during IR, and may act by a variety of not well understood biochemical mechanisms which ultimately lead to cell damage and tissue failure.

Thiol-containing compounds have an essential role in many biochemical reactions due to their ability to be easily oxidised and then quickly regenerated. Main representatives are glutathione, lipoic acid and thioredoxin which are synthesised de novo in mammalian cells. N-acetylcysteine and Bucillamine are synthetic thiols which have been administered in experimental and clinical studies for treatment of conditions associated with oxidative stress. Ischemia and reperfusion (I/R) injury is characterised by significant oxidative stress, characteristic changes in the antioxidant system and organ injury leading to significant morbidity and mortality. I/R occurs in a variety of clinical settings such as liver resection, organ transplantation, haemorrhagic shock with fluid resuscitation, heart surgery, myocardial infarction followed by reperfusion and laparoscopic surgery. In these circumstances, the administration of antioxidant agents such as thiols, could provide protection from the harmful effects of I/R injury. However, the ability of thiol compounds to reduce free radicals is associated with the formation of thiyl radicals and the rate and efficiency of removal of thiyl radicals has a critical effect on antioxidant or prooxidant actions of thiols in the cells. The aim of this review is to present the mechanisms by which thiols act as antioxidants and signalling molecules and the experimental and clinical evidence regarding their role in I/R injury with a particular emphasis on liver I/R. The current evidence suggests that thiols ameliorate I/R injury and that their clinical significance should be further evaluated in large scale randomised clinical trials.

Oxidative and nitrosative stress triggers DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP). One of the key triggers of DNA single strand breakage in pathophysiological conditions is peroxynitrite, a reactive species produced from the reaction of nitric oxide and superoxide. Activation of PARP can dramatically lower the intracellular concentration of its substrate, nicotinamide adenine dinucleotide, thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. Here we review the role of PARP in various forms of liver injury.

This review highlights recent advances in our understanding of intracellular mechanisms underlying programmed cell death in hepatic ischemia / reperfusion injury. A range of molecules have been tested with the intention to block the pathways of programmed cell death at different levels and to thereby enhance viability of the liver in surgical procedures including liver transplantation. Cellular death receptors, the mitochondrial pathway of apoptosis, p53, mitogen- activated protein kinases (MAPKs) and intracellular proteases all present potential targets for pharmaceutical agents to prevent ischemia induced cell death in the liver. Although evidence has been provided for effective inhibition of injury and improvement of survival by such agents, an optimal treatment strategy remains to be developed.

Liver ischemia-reperfusion injury is characterized by cell necrosis and apoptosis and by profound modifications in the extracellular matrix (ECM). During the complex series of events that take place both during ischemia and when normal blood flow is restored (reperfusion), a concerted regulation of release and activation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) mainly by stellate cells, Kupffer cells and inflammatory cells leads first to endothelial cell injury and subsequent infiltration of neutrophils into the wounded area. Later, MMP activation causes degradation of extracellular matrix components of the liver, mainly collagen and fibronectin, altering tissue architecture. The fibrosis that can result after liver injury is also dependent on the imbalance between MMPs and TIMPs and to new collagen deposition. Several experimental models of liver ischemia-reperfusion injury have demonstrated protective effects of MMP inhibitors in terms of cell necrosis, apoptosis and rearrangement of the extracellular matrix. This review summarizes current knowledge of MMP biology, with particular attention to the most recent evidence of novel, non-extracellular matrix MMP substrates involved in inflammation and cell cycle regulation. An overview of MMP and TIMP expression and activation in hepatic ischemia- reperfusion injury is provided. The analysis of such provides a rational basis for MMP inhibition as a viable strategy to prevent liver injury.

Ischemia reperfusion (IR) of the liver is a multifactorial process that, at least in part, is responsible for the morbidity associated with major liver surgery under occlusion of the portal triad with the Pringle maneuver, total vascular exclusion or after liver transplantation. Surgeons are confronted with IR injury (IRI) more often than they anticipate. Although the human body has its own defense system, understanding the pathophysiology of IRI is essential for the surgeon in preventing and/or treating the reperfusion injury in common clinical practice. Several endogenous mechanisms exist to overcome IRI and a large number of pharmacological agents have also been found to confer protection against ischemic injury in the liver. They either blocked the injurious pathways directly or they subjected the liver to preconditioning. Prostaglandins (PGs) are a group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase (COX) pathway. They are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis and are produced in most tissues of the body, although the liver has emerged as the major organ participating in the synthesis, degradation and elimination of arachidonate products of systemic origin. PGs are released through the prostaglandin transporter on the cell's plasma membrane. During the last decade intensive work on the cytoprotective effects of PGs on livers suffering from IRI have been well documented. Prostaglandins confer their protective effects on IR-injured livers mainly by inhibiting the generation of reactive oxygen species, preventing leukocyte migration, reducing the synthesis or production of membrane degradation products, improving hepatic insulin and lipid metabolism, and regulating the production of inflammatory cytokines and cell adhesion molecules. Production of PGs have been found essential also soon after partial hepatectomy for hepatocyte proliferation. Liver, ischemia reperfusion and prostaglandins are intimately related; their interaction remains to be fully understood. The present review highlights the accumulation of recent advances in this topic.

Glycine is a non-essential amino acid which is cheap, easily available and relatively non-toxic. It is composed of a single carbon attached to an amino and a carboxyl group, with a molecular weight of 75. It is involved in the production of bile, nucleic acids, porphyrins and creatine phosphate. It is part of the normal human diet and is used clinically, as an irrigant solution in urological and gynaecological procedures. Glycine has broad spectrum anti-inflammatory, cytoprotective and immunomodulatory properties whose therapeutic role has largely been un-investigated. Since the demonstration of its cytoprotective effect on hypoxic cultured renal tubule cells, further research has established its mechanism of anti-inflammatory action, which depends on stimulation of glycine sensitive chloride channel receptors on the cell membrane. The mechanism of non-specific cytoprotective effect which is present even in chloride and calcium free media is not clear. However glycine is currently being used experimentally, in human liver transplant recipients and has been shown to be beneficial in animal models of ischemia-reperfusion injury (IRI) in liver and several other organs. This review addresses the properties of glycine, its mechanism of action and its role in modulating IRI with special reference to the liver, with the aim of stimulating translational research into the potential role of glycine as a pharmaceutical agent.

Ischemia and reperfusion injury (IRI) is a prime antigen-independent inflammatory factor in the dysfunction of liver transplants. Despite improved allograft preservation and surgical techniques, IRI can still cause up to 10% of early orthotopic liver transplant failure, and can lead to a higher incidence of both acute and chronic graft rejection. Recent advances in gene transfer have resulted in a reduction or inhibition of liver IRI in several experimental models. This review summarizes the development of existing and potential approaches to human gene therapy. These studies aimed at ameliorating I/R injury are focused on the cytoprotective effects in transplant recipients by induction of anti-apoptotic or protective genes, immunoregulation of cytokines or blockade of signaling transduction pathway in graft cells. Although this review focuses on the application of viral mediated gene therapy, new non-viral gene transfer techniques, such as RNA interference (RNAi) application, are discussed. Future advances in gene therapy technology should result in fewer side effects, and thus more acceptable for clinical application, and more successful for organ transplantation.

It has been shown that capsaicin-sensitive afferent fibers play a crucial role in acute gastroprotection. Release of neurotransmitters such as calcitonin gene-related peptide (CGRP) and the consequent increase in mucosal blood flow have been identified as key factors in the protective effect of the stimulation of these fibers by capsaicin. Conversely the involvement of sensory nerves in the process of tissue repair after acute and chronic gastric mucosal damage has remained largely unexplored. Some studies, however, while demonstrating that the process of rapid repair (restitution) of the gastric mucosa damaged by ethanol is unaffected by capsaicin pretreatment, have shown that the recovery of gastric integrity after mucosal damage induced by sodium taurocholate or monochloramine, a known cytotoxic agent present in H. pylori patients, requires an intact sensory function and the maintenance of an adequate blood supply. In addition, a delayed healing (up to 1 week) of HCl-induced gastric lesions has been reported in capsaicin-deafferented rats, in association with a selective impairment of the hyperemic response to acid. Healing of gastric lesions induced by indomethacin, ischaemia and reperfusion, water restraint stress or concentrated ethanol was delayed in animals with functional ablation of sensory nerves. In a well-validated model, such as chronic gastric ulcers induced in rats by subserosal injection of acetic acid whose lesions last up to 4 weeks, the chemical ablation of sensory neurons negatively interferes with the process of chronic ulcer healing. The delay in ulcer healing was found to be associated with a persistent decrease in tissue levels of gastric CGRP and with a change of inflammatory mediators and growth factors, while gastric secretion and emptying were not concomitantly affected. Taken together, these data suggest that capsaicin-sensitive afferent nerves may play a role in the process of ulcer healing by mediating the hyperemic response through the release of CGRP and facilitating the acid disposal in the mucosa. From a therapeutic perspective, it is obvious that the compound acting on this system could have a role in the healing processes of the stomach damage.

Lithium augmentation refers to the addition of lithium to an antidepressant in the acute treatment phase of patients with depressive episodes who have failed to respond satisfactorily to treatment with antidepressant monotherapy. This article reviews the clinical evidence and hypotheses on the mode of action of lithium augmentation. For this purpose, studies were identified by searching Medline and by scanning the references of published reviews and standard textbooks. With regard to efficacy, 28 prospective studies (with a total of 838 depressed patients) were identified. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation. A recent meta-analysis including only double-blind, placebo-controlled trials (N = 9) provided firm evidence that lithium augmentation has a statistically significant effect on response rate compared to placebo, and showed that lithium augmentation should be administered for at least 2 weeks to allow assessment of the patient' s response. A recent double-blind, placebo-controlled trial revealed that responders to lithium augmentation should be maintained on the lithium-antidepressant combination for a minimum of 12 months. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly through a synergistic action of lithium and the antidepressant on brain 5-HT pathways. Neuroendocrine studies in humans on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined dexamethasone/CRH test. These results are in contrast to the established decline of HPA system activity during treatment with antidepressants. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment.