Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, Vol. 3, No. 3, 2004
Contents
Guest Editor: Bahar Tunētan
Antioxidant Properties of Nitric
Oxide in Cellular Physiological and Pathophysiological Mechanisms. The
Implications of Biological Balance between ·NO and Oxidative Stress Pp. 181-188
Lisa A. Ridnour, Douglas D.
Thomas, Daniele Mancardi, Sonia Donzelli, Nazerrano Paolocci, Pasquale
Pagliaro, Katrina M. Miranda, Murali Krishna, John Fukuto, Matthew B. Grisham,
James B. Mitchell, Michael G. Espey and David A. Wink
The Physiology of Nitric Oxide:
Control and Consequences Pp. 189-205
Ingrid Fleming and Rudi Busse
Pathophysiological Roles of
Nitric Oxide: In the Heart and the Coronary Vasculature Pp. 207-216
C. Dessy and O. Feron
Nitric Oxide and Inflammation Pp. 217-222
C.C. Wu
The Role of Nitric Oxide in
Autoimmune Diseases Pp. 223-238
Klaus-Dietrich Kroncke
Inhibitors of Nitrogen Oxide
Species Production in Animal Models of Inflammation and Future Directions for Therapy
in Inflammatory Disorders Pp. 239-259
Francois Feihl, Mauro Oddo,
Bernard Waeber and Lucas Liaudet
Effect of Inhibitors of Nitric
Oxide in Animal Models and Future Directions for Therapy in Inflammatory
Disorders Pp.
261-270
Salvatore Cuzzocrea
The Use of Nitric Oxide Synthase Inhibitors
in Inflammatory Diseases: A Novel Class of Anti-Inflammatory Agents Pp. 271-301
Bahar Tunētan and Sedat Altug
Abstracts
[Back
to top] Antioxidant Properties of
Nitric Oxide in Cellular Physiological and Pathophysiological Mechanisms. The
Implications of Biological Balance between ·NO and Oxidative Stress
Lisa A. Ridnour, Douglas D. Thomas, Daniele Mancardi, Sonia
Donzelli, Nazerrano Paolocci, Pasquale Pagliaro, Katrina M. Miranda, Murali
Krishna, John Fukuto, Matthew B. Grisham, James B. Mitchell, Michael G. Espey
and David A. Wink
The function of nitric oxide (·NO) in pathophysiology remains confounding as both protective and cytotoxic effects of ·NO have been demonstrated in many disease processes. Nitric oxide chemistry culminating in the generation of oxidative as well as itrosative intermediates have generally been proposed as mediators of pathophysiology and have overshadowed the antioxidant capabilities of ·NO. However, the counteracting role of ·NO in providing a balance under conditions of oxidative and nitrosative stress has been underappreciated. The purpose of this review is the discussion of the role of ·NO as an antioxidant and interceptor of more potent reactive intermediates in normal physiology and disease.
[Back
to top] The Physiology of Nitric Oxide: Control and Consequences
Ingrid Fleming and Rudi Busse
Since its recognition as an endothelium-derived relaxing factor, the control and consequences of nitric oxide (NO) production has been investigated intensely. NO is not simply a vasodilator or regulator of smooth muscle tone but is a potent anti-platelet agent, neuromodulator and regulator of gene expression. This article reviews the mechanisms (intracellular Ca2+, phosphorylation and protein-protein interaction) that regulate the activity of each of the NO synthase isoforms and describes the physiology of NO in the circulation, kidney, skeletal muscle as well as in endocrine, immune and nervous systems.
[Back
to top] Pathophysiological Roles of Nitric Oxide: In the Heart and
the Coronary Vasculature
C. Dessy and O. Feron
Nitric oxide is a key player among the numerous mediators of endothelial homeostasis and cardiac contractility and is thereby involved in the pathogenic processes leading to vascular and myocardial dysfunctions. Although none of the current paradigms would elevate the influence of NO on cardiac contraction to the level of that of e.g., catecholamines or increased calcium, this unusual signaling molecule can modulate virtually all the regulatory steps of excitationcontraction coupling and influence the course of cardiac decompensation. Not only alterations in spatial confinement or post-translational modifications but also changes in the abundance of one of the three NOS isoforms may result in profound cellular disturbancies that participate in the endothelial and contractile dysfunctions leading to cardiovascular diseases.
[Back
to top] Nitric Oxide and Inflammation
C.C. Wu
Nitric oxide (NO) is a very labile molecule of ubiquitous significance in biological systems in general. During the past two decades, NO has been recognized as one of the most versatile players in immune function. This diatomic molecule is normally produced by constitutive NO synthase and plays an important role in physiological regulation of nerve transmission and cardiovascular function. In contrast, an enormous and uncontrollable amount of NO, is synthesized by inducible NO synthase in activated immune cells during inflammation. Although the production of NO in inflammation has been described in numerous studies, the equivocal role for NO in vs. during an inflammatory response is not clearly defined. For example, when produced in excess, NO or its metabolites may not only be cytotoxic to host cells but also mediate local host defense mechanisms. As a result, NO has been nicknamed both murderer and mediator. This article reviews these two apparently opposing aspects of NO action during infection in the human system. This review deviates from post-1990 authoritative reviews in attempting to highlight important differences in the reaction of NO with oxygen or superoxide when fluxes of NO are dramatically enhanced reactions, which may predominate during active inflammation. This article proposes that in humans, the physiological chemistry of NO and its metabolites allow one to identify which of the many NO-dependent reactions contribute to the modulation of inflammatory response, and may help scientists in the design of new therapeutic agents for the treatment of inflammatory diseases.
[Back
to top] The Role of Nitric Oxide in Autoimmune Diseases
Klaus-Dietrich Kroncke
Comprising multiple organ-specific to systemic
disorders and symptoms, autoimmune diseases include type 1 diabetes, rheumatoid
arthritis, multiple sclerosis, systemic lupus erythematosus, scleroderma,
thyroiditis, and others. There are also implications of autoimmune pathology in
common health problems such as arteriosclerosis, inflammatory bowel diseases,
psoriasis, schizophrenia, and certain types of infertility. Protein expression
of the inducible nitric oxide synthase (iNOS) has been found in the majority of
the above mentioned human autoimmune diseases or in animal models of these
diseases, mostly in inflammatory cell infiltrates like activated macrophages,
but also in organ-specific epithelial cells or in parenchymal cells. The role
of NO in inflammation is very complex. On the one hand, NO mediates important
direct cytotoxic effects and on the other hand it modulates immunological
functions, which in the setting of autoimmune diseases may be beneficial.
Current knowledge regarding the role of iNOS-derived NO in various human
autoimmune diseases as well as in the respective animals models is reviewed
here.
[Back
to top]
Inhibitors of Nitrogen Oxide Species Production in Animal Models
of Inflammation and Future Directions for Therapy in Inflammatory Disorders
Francois Feihl, Mauro Oddo, Bernard Waeber and Lucas Liaudet
Nitric oxide (NO) and inflammation
interact at many levels. First, NO produced in low, physiological levels by
vascular endothelial cells under the control of the constitutive endothelial
nitric oxide synthase (eNOS) tends to inhibit endothelial-leucocyte
interactions. Thus, pharmacologic interventions, which block eNOS are
counterproductive in inflammatory diseases. Second, inflammation is
characteristically associated with the stimulated expression of the inducible
isoform of nitric oxide synthase (iNOS), leading to production of large amounts
of NO for extended period of time in many cell types. These large amounts of NO
potentially contribute to tissue damage through the generation of toxic
reactive nitrogen species such as higher nitrogen oxides and peroxynitrite.
Therefore, it could be of therapeutic value to selectively inhibit iNOS, while
leaving intact the
activity of eNOS. In recent years, considerable
progress has occurred in the molecular design of highly potent and highly
selective inhibitors of iNOS. However, effects of these agents in specific
disease conditions is not readily predictable, because the interactions of NO
and inflammation are considerably more intricate than just indicated. For
example, the activation of nuclear factor kappa B (NF-kB), an essential pathway for induction of an
inflammatory cellular phenotype, may either by enhanced or inhibited by NO,
depending on particular conditions. In addition, NO has a complex influence on
the production of inflammatory prostanoids. NO is also a player in acquired immunity,
for example by tilting the Th1/Th2 balance in favour of Th2 responses. Finally,
NO is an important effector in the defense against at least some invading
pathogens. Here we provide a detailed review of efforts made at characterizing
the effects of disrupting the function of iNOS, by either genetic or
pharmacologic means, in three classes of experimental paradigms: 1) models of
arthritis, 2) models of inflammatory bowel disease, and 3) models of
generalized inflammation induced by endotoxemia or bacterial sepsis. The
accrued evidence in each of these cases suggests that the contribution of NO to
pathophysiology of inflammatory diseases is highly heterogeneous, and therefore
difficult to target therapeutically by the presently available means.
[Back
to top]
Effect of Inhibitors of Nitric Oxide in Animal Models and Future Directions for
Therapy in Inflammatory Disorders
Salvatore Cuzzocrea
The aim of the current article is to overview
the recent developments in the field of inflammation, as it relates to the
roles of nitric oxide (NO) and peroxynitrite in the pathogenesis of this
condition. The first part of the review focuses on the roles of NO and
peroxynitrite, a reactive oxidant produced from the reaction of NO and superoxide.
The second part of the review deals with the novel findings related to the
recently identified regulatory roles of the inducible isoform of nitric oxide
synthase (iNOS) in the expression of pro-inflammatory mediators in
inflammation. Reactive oxygen species can initiate a wide range of toxic
oxidative reactions. These include initiation of lipid peroxidation, direct
inhibition of mitochondrial respiratory chain enzymes, inactivation of
glyceraldehyde-3phosphate dehydrogenase, inhibition of membrane sodium/potassium
ATP-ase activity, inactivation of membrane sodium channels, and other oxidative
modifications of proteins. All these toxicities are likely to play a role in
the pathophysiology of inflammation. Reactive oxygen species (e.g., superoxide,
peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential
reactants capable of initiating DNA single strand breakage, with subsequent
activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading
to eventual severe energy depletion of the cells, and necrotic-type cell death.
Recently , it has been demonstrated that iNOS inhibitor prevents the activation
of poly (ADP ribose) synthetase, and prevents the organ injury associated with
inflammation. Although the severity and duration of inflammation may dictate
the timing and extent of NOS expression, it is now evident that the
upregulation of NOS can take place during sustained inflammation.
Pharmacological inhibition of iNOS or genetic inactivation of NOS (iNOS
knockout mice) attenuates the activation of the transcription factors nuclear
factor kappa B (NFKB) and Signal Transducer and Activator of Transcription 3
(STAT3), and ameliorates the increases in G-CSF messenger RNA levels in the
tissue. Thus, induced nitric oxide, in addition to being a "final common
mediator" of inflammation, is essential for the upregulation of the
inflammatory response. Furthermore, a picture of a pathway is evolving that
contributes to tissue damage both directly via the formation of peroxynitrite,
with its associated toxicities, and indirectly through the amplification of the
inflammatory response.
[Back
to top]
The Use of Nitric Oxide Synthase Inhibitors in Inflammatory Diseases: A Novel
Class of Anti-Inflammatory Agents
Bahar Tunētan and Sedat Altug
Nitric oxide (NO) is produced enzymatically in
numerous tissues and considered as important mediator of many physiological and
pathophysiological processes. NO is synthesized from L-arginine by three isoforms
of the enzyme NO synthase (NOS). Among these three established isozymes of NOS,
neuronal NOS (nNOS) and endothelial NOS (eNOS) are constitutive (cNOS) and
low-output enzymes whose physiological functions are signal transduction. The
third form of NOS, inducible NOS (iNOS), is constitutively expressed only in
certain tissues and more typically synthesized in response to inflammatory or
pro-inflammatory mediators. Although considerable evidences implicate the role
of NO in the pathophysiology of inflammatory processes, there are contradictory
reports in the literature concerning its role as an anti-inflammatory or
pro-inflammatory agent. It is likely that NO from eNOS plays a role in the
early stages of inflammation whereas NO from iNOS contributes to many aspects
of chronic inflammation. Therefore, the use of selective iNOS inhibitors may be
beneficial for the treatment of inflammatory processes. On the other hand,
development of selective iNOS inhibitors will have to address potential
problems related to inhibition of NO derived from cNOS in situations in which
this mediator may be beneficial. In this review, contribution of NO to the
pathophysiology of inflammatory conditions and clinical use of substrate-based
NOS inhibitors, including arginine analogues and amidinecontaining inhibitors
as potential anti-inflammatory agents in a variety of inflammatory diseases
will be discussed.