| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 23, 2006
Contents
Pharmacological Modulation of Liver Ischemia –
Reperfusion Injury
Executive Editors: G.K. Glantzounis, D.P. Mikhailidis,
A.M. Seifalian and B.R. Davidson
Editorial Pp. 2863-2865
The Role of Cytokines in Pharmacological Modulation of Hepatic
Ischemia/Reperfusion Injury Pp. 2867-2873
T.L. Husted and A.B. Lentsch
[Abstract]
Oxidative Stress in Hepatic Ischemia-Reperfusion
Injury: The Role of Antioxidants and Iron Chelating Compounds
Pp. 2875-2890
D. Galaris, A. Barbouti and P. Korantzopoulos
[Abstract]
The Role of Thiols in Liver Ischemia-Reperfusion
Injury Pp. 2891-2901
G.K. Glantzounis, W. Yang, R.S. Koti, D.P. Mikhailidis,
A.M. Seifalian and B.R. Davidson
[Abstract]
Role of the Peroxynitrite - Poly (ADP-Ribose)
Polymerase Pathway in the Pathogenesis of Liver Injury
Pp. 2903-2910
D. Gerö
and C. Szabó
[Abstract]
Blocking the Path to Death Anti-Apoptotic Molecules
in Ischemia / Reperfusion Injury of the Liver Pp.
2911-2921
P. Georgiev, F. Dahm, R. Graf and P.-A. Clavien
[Abstract]
The Role of Matrix Metalloproteinase Inhibitors
in Ischemia Reperfusion Injury in the Liver Pp. 2923-2934
S. Viappiani, M. Sariahmetoglu and R. Schulz
[Abstract]
The Role of Prostaglandins in Liver Ischemia-Reperfusion
Injury Pp. 2935-2951
M.A. Hossain, H. Wakabayashi, K. Izuishi, K. Okano, S.
Yachida and H. Maeta
[Abstract]
The Role of Glycine in Hepatic Ischemia-Reperfusion
Injury Pp. 2953-2967
M.M. Habib, H.J.F. Hodgson and B.R. Davidson
[Abstract]
Gene Therapy in Liver Ischemia and Reperfusion
Injury Pp. 2969-2975
B. Ke, G.S. Lipshutz and J.W. Kupiec-Weglinski
[Abstract]
General Articles
Role of Sensory Neurons in Restitution and Healing
of Gastric Ulcers Pp. 2977-2984
S. Evangelista
[Abstract]
Efficacy and Mechanisms of Action of Lithium Augmentation
in Refractory Major Depression Pp. 2985-2992
T. Bschor and M. Bauer
[Abstract]
Abstracts
[Back
to top]
Editorial
Pharmacological Modulation of Liver Ischemia – Reperfusion
Injury
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. Mammalian cells also have an in-built system for dealing
with oxidative stress by the synthesis of thiol containing
compounds. Glantzounis et al. [14]
consider the role of thiols in normal cellular metabolism
and review the growing experimental and clinical evidence
that synthetic thiols will have a future clinical role in
ameliorating liver I/R injury. However these strategies may
have been focusing on only one aspect of free radical injury
with the full importance of reactive nitrogen species having
only recently been highlighted.
Gerö
et al. [15] discuss the effect of peroxynitrite on DNA
single strand breakage with the subsequent activation of the
nuclear enzyme poly(ADP-ribose) polymerase (PARP) that can
lead to a failure of cellular energy metabolism. Pharmacological
prevention of peroxynitrite formation or PARP inhibitors are
suggested as future therapeutic targets.
Although both ROS and RNS production may be important their
significance relates to their ability to produce cell injury
leading to cell death. Georgiev et al.
[16], summarize the intracellular mechanisms leading to programmed
cell death in liver IRI. Experimental evidence supports the
beneficial effects of anti-apoptotic strategies. Hepatocyte
viability and apoptosis is closely linked to changes to sinusoidal
membrane permeability and neutrophil migration from the vascular
compartment to the interstitial tissues. This process is actively
controlled by remodeling of the interstitium under the influence
of matrix metalloproteinases (MMPs) and tissue inhibitors
of metalloproteinases (TIMPs). Viappiani
et al. [17] have defined the steps involved and review
the experimental studies on the role of MMPs and their inhibitors
in liver IRI. New therapeutic strategies are proposed and
recent evidence linking MMP,s with cell cycle control are
discussed.
The search for a single therapeutic target to modulate liver
IR as defined above may be unrealistic given the diverse inter-relationships
and multiple factors involved. An alternative approach is
to utilize drugs which have a range of therapeutic roles.
Prostaglandins inhibit ROS formation and leukocyte migration
and regulate the production of inflammatory cytokines and
cell adhesion molecules. Hossain et al.
[18] reviews these and other mechanisms of action in liver
IR and critically evaluates the experimental and clinical
studies which support their clinical application. Conflicting
studies on efficacy may be related to methods of administration
and combining prostaglandins with other agents is suggested
as a possible future direction. Glycine is a non-essential
amino acid which also has multiple properties including anti-inflammatory,
cytoprotective and immunomodulation but whose therapeutic
role has undergone limited investigations. The review by Habib
et al. [19] highlights these roles and provides experimental
evidence to support more extensive investigations in liver
I/R injury.
In contrast to the multiple diverse functions of prostaglandins
and glycine, gene therapy strategies allow precise targeting
of a single step in the IR cascade, allowing its role and
biological importance to be identified and information provided
for future gene targeted therapy in human liver IR. Ke
et al. [20] discusses the major developments in this
field which have occurred over the last decade and how this
approach has identified novel therapeutic targets.
This special issue of Current Pharmaceutical Design provides
comprehensive up to date information about the mechanisms
involved in liver IRI and highlights our current understanding
of the complex pathways involved. The experimental and clinical
evidence on beneficial therapeutic strategies have been reviewed
in detail and future developments identified. Although the
pathways responsible for liver IRI have been analyzed separately
for ease of reference this is clearly a cross linked multifactorial
process and effective strategies may require carefully measured
alteration to several biochemical pathways. The considerable
morbidity and mortality associated with liver IR in clinical
practice should provide the stimulus to further research and
development in this exciting field.
References
[1] McCord JM: Oxygen-derived free radicals in postischemic
tissue injury. N Engl J Med 1985; 312: 159-63.
[2] Seifalian AM, Chidambaram V, Rolles K, Davidson BR. In
vivo demonstration of impaired microcirculation in steatotic
human liver grafts. Liver Transpl Surg. 1998; 4: 71-77.
[3] Selzner M, Clavien PA. Fatty liver in liver transplantation
and surgery. Semin Liver Dis 2001; 21: 105-13.
[4] Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic
ischemia/reperfusion injury--a fresh look. Exp Mol Pathol
2003; 74: 86-93.
[5] Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion
injury and preconditioning. Am J Physiol Gastrointest Liver
Physiol 2003; 284: G15-G26.
[6] Glantzounis GK, Salacinski HJ, Yang W, Davidson BR, Seifalian
AM. The contemporary role of antioxidant therapy in attenuating
liver ischemia-reperfusion injury: A review. Liver Transpl
2005; 11: 1031-47.
[7] Lentsch AB, Kato A, Yoshidome H, McMasters KM, Edwards
MJ. Inflammatory mechanisms and therapeutic strategies for
warm hepatic ischemia/reperfusion injury. Hepatology 2000;
32: 169-73.
[8] Banga NR, Homer-Vanniasinkam S, Graham A, Al-Mukhtar A,
White SA, Prasad KR. Ischaemic preconditioning in transplantation
and major resection of the liver. Br J Surg 2005; 92: 528-38.
[9] Kharbanda RK, Mortensen UM, White PA, Kristiansen SB,
Schmidt MR, Hoschtitzky JA, et al. Transient limb
ischemia induces remote ischemic preconditioning in vivo.
Circulation 2002; 106: 2881-83.
[10] Koti RS, Seifalian AM, Davidson BR. Protection of the
liver by ischemic preconditioning: a review of mechanisms
and clinical applications. Dig Surg 2003; 20: 383-96.
[11] Husted TL, Lentsch AB. The role of cytokines in pharmacological
modulation of hepatic ischemia/reperfusion injury. Curr Pharm
Des 2006; 12(23): 2867-2873.
[12] Sies H. Oxidative stress II. oxidants and antioxidants.
Academic Press, London 1991.
[13] Galaris D, Barbouti A, Korantzopoulos P. Oxidative stress
in hepatic ischemia-reperfusion injury: the role of antioxidants
and Iron chelating compounds. Curr Pharm Des 2006; 12(23):
2875-2890.
[14] Glantzounis GK, Yang W, Koti RS, Mikhailidis DP, Seifalian
AM, Davidson BR. The role of thiols in liver ischemia-reperfusion
injury. Curr Pharm Des 2006; 12(23): 2891-2901.
[15] Gerö
D, Szabó C. Role of the peroxynitrite-poly (ADP-ribose)
polymerase pathway in the pathogenesis of liver injury. Curr
Pharm Des 2006; 12(23): 2903-2910.
[16] Georgiev P, Dahm F, Graf P, Clavien P.-A. Blocking the
path to death. Anti-apoptotic molecules in ischemia/reperfusion
injury of the liver. Curr Pharm Des 2006; 12(23): 2911-2921.
[17] Viappiani S, Sariahmetoglu M, Schulz R. The role of matrix
metalloproteinase inhibitors in ischemia-reperfusion injury
in the liver. Curr Pharm Des 2006; 12(23): 2923-2934.
[18] Hossain MA, Wakabayashi H, Izuishi K, Okano K, Yashida
S, Maeta H. The role of prostaglandins in liver ischemia-reperfusion
injury. Curr Pharm Des 2006; 12(23): 2935-2951.
[19] Habib MM, Hodgson HJF, Davidson BR. The role of Glycine
in hepatic ischemia-reperfusion injury. Curr Pharm Des 2006;
12(23): 2953-2967.
[20] Ke B, Lipshutz GS, Kupiec-Weglinski JW. Gene therapy
in liver ischemia and reperfusion injury. Curr Pharm Des 2006;
12(23): 2969-2975.
G.K. Glantzounis
A.M. Seifalian
B.R. Davidson
Hepatopancreaticobiliary and Liver Transplant Unit,
University Department of Surgery,
Royal Free and University College London Medical School,
University College London and
Royal Free Hampstead NHS Trust,
London,
UK
D.P. Mikhailidis
Department of Clinical Biochemistry
Royal Free and University College
London Medical School
University College London and
Royal Free Hampstead NHS Trust
London
UK
[Back to top]
The Role of Cytokines in Pharmacological Modulation of Hepatic
Ischemia/Reperfusion Injury
T.L. Husted and A.B. Lentsch
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.
[Back to top]
Oxidative Stress in Hepatic Ischemia-Reperfusion
Injury: The Role of Antioxidants and Iron Chelating Compounds
D. Galaris, A. Barbouti and P. Korantzopoulos
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.
[Back to top]
The Role of Thiols in Liver Ischemia-Reperfusion
Injury
G.K. Glantzounis, W. Yang, R.S. Koti, D.P. Mikhailidis,
A.M. Seifalian and B.R. Davidson
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.
[Back to top]
Role of the Peroxynitrite - Poly (ADP-Ribose)
Polymerase Pathway in the Pathogenesis of Liver Injury
D. Gerö
and C. Szabó
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.
[Back to top]
Blocking the Path to Death Anti-Apoptotic Molecules
in Ischemia / Reperfusion Injury of the Liver
P. Georgiev, F. Dahm, R. Graf and P.-A. Clavien
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.
[Back to top]
The Role of Matrix Metalloproteinase Inhibitors
in Ischemia Reperfusion Injury in the Liver
S. Viappiani, M. Sariahmetoglu and R. Schulz
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.
[Back to top]
The Role of Prostaglandins in Liver Ischemia-Reperfusion
Injury
M.A. Hossain, H. Wakabayashi, K. Izuishi, K. Okano, S.
Yachida and H. Maeta
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 pro-liferation.
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.
[Back to top]
The Role of Glycine in Hepatic Ischemia-Reperfusion
Injury
M.M. Habib, H.J.F. Hodgson and B.R. Davidson
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.
[Back to top]
Gene Therapy in Liver Ischemia and Reperfusion
Injury
B. Ke, G.S. Lipshutz and J.W. Kupiec-Weglinski
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.
[Back to top]
Role of Sensory Neurons in Restitution and Healing
of Gastric Ulcers
S. Evangelista
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 indo-methacin, 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.
[Back to top]
Efficacy and Mechanisms of Action of Lithium Augmentation
in Refractory Major Depression
T. Bschor and M. Bauer
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.
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