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Inflammation & Allergy -
Drug Targets
(Formerly 'Current Drug Targets - Inflammation & Allergy')
ISSN: 1871-5281
Inflammation & Allergy
- Drug Targets
Volume 5, Number 2, April 2006
Contents
Nitric Oxide and Lipoxins: Role in Inflammation and
Defence
Guest Editor: Stefano Fiorucci
Editorial Pp. 79
Lipid Mediators: Lipoxin and Aspirin-Triggered 15- Epi
Lipoxins Pp. 81-90
Mario Romano
[Abstract]
Lipoxin and Synthetic Lipoxin Analogs: An Overview
of Anti Inflammatory Functions and New Concepts in Immunomodulation
Pp. 91-106
John F. Parkinson
[Abstract]
Novel Aspects of Annexin 1 and Glucocorticoid Biology:
Intersection with Nitric Oxide and the Lipoxin Receptor Pp.
107-114
Mauro Perretti and Fulvio D’Acquisto
[Abstract]
Nitric Oxide and Inflammation Pp. 115-119
Giuseppe Cirino, Eleonora Distrutti and John L. Wallace
[Abstract]
NO-NSAIDs: From Inflammatory Mediators to Clinical
Readouts Pp. 121-131
Stefano Fiorucci and Elisabetta Antonelli
[Abstract]
Nitric Oxide, Aspirin-Triggered Lipoxins and NO-Aspirin
in Gastric Protection Pp. 133-137
John L. Wallace
[Abstract]
Abstracts
[Back to top]
Editorial
The focus of this special issue of Inflammation &
Allergy - Drug Targets is on anti-inflammation.
The inflammatory response protects the body against infection
and injury, but can itself become deregulated with deleterious
consequences to the host. Several endogenous biochemical pathways
activated during defense reactions can counter-regulate inflammation.
It is increasingly recognized that chronic inflammation develops
as a consequence of the failure of these systems to attenuate
generation of inflammatory mediators. Bioactive eicosanoids
represent the main mediators of inflammation. Synthesis of
the eicosanoids (Reviewed in this issue by Dr. Mario Romano)
originates when arachidonic acid is converted to the prostaglandins
through the prostaglandin synthase pathways. Arachidonic acid
can also be oxygenated by lipoxygenases to form HPETEs. 5-lipoxygenase
catalyzes the production of leukotriene (LT) A4, which is
in turn hydrolyzed to produce LTB4; alternatively, the addition
of a glutathione moiety in the presence of glutathione S-transferase
produces LTC4 and LTD4. In contrast to the LTs and the prostaglandins,
the lipoxins (LXs), an acronym for lipoxygenase interaction
products, are endogenously produced eicosanoids with anti-inflammatory
actions. LX synthesis begins with the oxygenation of arachidonic
acid by 15-lipoxygenase to form 15-HETE. Within leukocytes,
15-HETE is converted to LXA4 by 5-lipoxygenase and epoxide
hydrase.
LXs were first identified by Charles Serhan and colleagues
in 1984 from purified fractions of leukocyte suspensions that
were coincubated with the ionophore A-23187 and 15-hydroperoxyeicosatetraenoic
acid. During the last 20 years, significant efforts have been
directed toward identifying the physiological actions of LXs
in the inflammatory response and to design metabolically stable
analogs that could have been used for therapeutic purposes
(Reviewed in this issue by Dr. John Parkinson). In contrast
to the proinflammatory eicosanoids, LXs are proposed to act
as endogenous "braking signals" in inflammation.
Aspirin not only inhibits eicosanoids generation but can also
trigger the formation of the 15-epi-LXs that are usually referred
to as the aspirin-triggered LXs (ATLs). Thus, cyclo-oxygenase-2
acetylation by aspirin modifies its activity to generate 15R-hydroxyeicosatetraenoic
acid, which can be oxygenated to produce 15(R)-epi-LXA4.
Similarly to LXA4,
ATL exerts potent anti-inflammatory actions. Synthetic ligands
of LXA4
and ATLs have facilitated the characterization of distinct
receptors for LXA4
that mediate the anti-inflammatory signals. These studies
provide evidence that ATLa can directly or indirectly modulate
T cell effector function in the setting of Th1- and Th2-dependent
inflammation and adaptive immunity. In addition, a surprising
interaction of LXs and glucocorticoids has been demonstrated
in the context of the broad anti-inflammatory activity of
these agents that represent the most potent endogenous anti-inflammatory
mediators in mammals (Reviewed by Dr. Mauro Perretti).
Nitric oxide (NO) is also regarded as an anti-inflammatory
mediator. NO, synthesized from L-arginine by a family of constitutive
and inducible NO synthases, is a small, diffusible, highly
reactive molecule that serves a variety of functions in the
cardiovascular system and accounts for most of the endothelium-dependent
vasodilation. NO is considered a double sword mediator, since
its excessive generation in the context of inflammatory states
leads to vasodilation a key hallmark of inflammation (Reviewed
by Dr. Giuseppe Cirino). In addition to controlling vascular
tone and vasodilation however, NO also regulates adhesive
interactions at the endothelium surface. Thus, exposure of
endothelial cells to NO inhibits E-selectin, intercellular
adhesion molecule and vascular cell adhesion molecule-1 expression,
limiting the release of secretable cytokines IL-6 and IL-8
and prevents nuclear translocation of nuclear factor (NF)-κB,
suggesting that similar to LXA4
and ATLs, NO might act as a braking signal in regulating vascular
inflammation.
Development of anti-inflammatory agents that limit eicosanoid
production and release NO seems the logical exploitation of
our increasing understanding of the cross-talk between pro-
and anti-inflammatory mediators. In the recent years, several
of these agents, called the COX-inhibitor NO-donating agents
(CINODs) have been reported (Reviewed by Dr. Stefano Fiorucci).
Interaction of NO-releasing aspirin with the LXs system, and
the ability of ATLs to trigger NO formation (Reviewed by Dr.
John Wallace), highlight the tight interaction between these
two functionally distinct families of mediators. This issue
is a journey through these mediators and describes how exploitation
of anti-inflammation can be used to treat human diseases.
A special thanks goes to all the authors who have accepted
the invitation to spend some of their time in writing these
reviews, and to Samina Khan, the Senior Manager Publications
at Bentham Science Publishers Ltd.
Stefano Fiorucci
University of Perugia
Italy
E-mail: fiorucci@unipg.it
[Back to top]
Lipid Mediators: Lipoxin and Aspirin-Triggered 15-
Epi Lipoxins
Mario Romano
Lipoxins (LX) and their 15-epimers, aspirin triggered lipoxins
(ATL) are emerging as major promoters of resolution of the
inflammatory reaction. These eicosanoids, that carry a tetraene
chromophore, derive from sequential lipoxygenase (LO) metabolism
of arachidonic acid. Three principal routes of LX/ATL biosynthesis
have been uncovered. One involves cooperation between 15-
and 5-LO, one other requires interactions between 12-and 5-LO
and a third is characterized by 5-LO transformation of intermediary
products generated by aspirin-acetylated cyclooxygenase (COX)-2.
Thus, in a large majority of cases the biosynthesis of these
eicosanois requires transcellular metabolic exchange during
cell-cell interactions. LX and ATL are rapidly metabolized
and inactivated by monocyte 15-hydroxyprostaglandin dehydrogenase
(PGDH). A number of stable analogs that resist inactivation
and retain biological activity has been synthesized. Accumulating
evidence suggests that these analogs may have a potential
therapeutic impact in a variety of diseases characterized
by neutrophil-mediated persistent inflammation, such as reperfusion
injury, gastro-intestinal and renal inflammatory disorders,
periodontitis. Clinical evaluation of LXA4
and 15-epi-LXA4
formation and their pharmacological regulation may be now
achieved using recently developed ELISA assays, that allow
large-scale measurements in human biological fluids.
[Back to top]
Lipoxin and Synthetic Lipoxin Analogs: An Overview
of Anti Inflammatory Functions and New Concepts in Immunomodulation
John F. Parkinson
Lipoxin A4
(LXA4)
and lipoxin B4
(LXB4)
were first identified in 1984 by Serhan and colleagues as
5- and 15-lipoxygenase interaction
products of activated leukocytes. Endogenous transcellular
biosynthesis of LXA4
and LXB4
occurs via interaction of leukocytes with epithelium,
endothelium or platelets. Acetylation of cyclooxygenase-2
(COX-2) by aspirin can trigger 15-epi-LXA4
(ATL) biosynthesis. Elucidating the pharmacological actions
of lipoxins and ATL was facilitated by total synthesis of
LXA4
in 1988 by Nicolaou and colleagues. In 1994, Fiore and colleagues
used [3H]-LXA4
to identify the cDNA for a human G-protein-coupled, high affinity
LXA4
and ATL receptor (ALX-R/FPRL-1), providing the first hints
for the molecular basis of lipoxin actions. The recognition
that lipoxins and ATL undergo rapid, prostaglandin dehydrogenase
(PGDH)–mediated metabolic inactivation led do the design
and synthesis of first-generation PGDH-resistant LXA4,
LXB4
and ATL analogs in 1995-1998 by Serhan, Petasis and colleagues.
These relatively stable pharmacological agents, together with
myeloid-specific ALX-R-expressing transgenic mice, have provided
powerful tools to explore lipoxin functions in vivo.
Here we briefly review the substantial body of evidence supporting
the lipoxin →
ALX-R pathway as a novel and potent mechanism for preventing/resolving
acute inflammation. Emphasis will also be placed on recent
findings that lipoxins play new roles in “immunomodulation”
via regulation of macrophage, dendritic cell, and
T-lymphocyte effector functions in the setting of polarized
T-helper cell responses (Th1
and Th2).
These studies suggest roles for lipoxins as novel regulators
of allergy and adaptive immunity and that lipoxins may have
therapeutic potential in chronic immune disorders.
[Back to top]
Novel Aspects of Annexin 1 and Glucocorticoid Biology:
Intersection with Nitric Oxide and the Lipoxin Receptor
Mauro Perretti and Fulvio D’Acquisto
This review will emphasize the concept of anti-inflammation
and propose that better understanding of the resolution phase
of the inflammatory response organized by the host against
inflammatory insults can lead to the identification of novel
targets for drug development. Under the umbrella of anti-inflammation,
we discuss here recent discoveries in the biology of annexin
1 and glucocorticoids. The fact that annexin 1 and another
anti-inflammatory mediator, lipoxin A4,
converge onto a specific membrane receptor (termed ALX) might
help understanding the resolution phase of inflammation, and
strengthen the use of this target for innovative drug development.
In addition, glucocorticoids (GC), historically linked to
annexin 1, are widely use in the clinical control of several
pathologies with an inflammatory etiology, though their use
is often burdened by several side effects. The development
of new GC with more specific or improved mechanisms, e.g.
the nitro-steroids, would go along this wave and, potentially,
could be of large applicability. The two mediators/targets
here illustrated are to be taken as examples of the clues
that the study of anti-inflammation might give to the pharmaceutical
industry for innovative drug discovery.
[Back to top]
Nitric Oxide and Inflammation
Giuseppe Cirino, Eleonora Distrutti and John L. Wallace
There are several pre-clinical studies on the involvement
of NO in inflammation. From this large amount of information
it is clear that virtually every cell and many immunological
parameters are modulated by NO. Thus, the final outcome is
that NO cannot be rigidly classified as an anti-inflammatory
or pro-inflammatory molecule.
This peculiar aspect of the pathophysiology of NO has hampered
the development of new drugs based on the concepts developed.
Recent therapeutic approach are targeted to increase endogenous
NO by activating the gene and some promising early data are
available. At the present stage one of the most promising
approach in the inflammation field is represented by a new
class of NO-releasing compounds namely NO-NSAIDs that have
recently enrolled in phase 2 clinical studies.
[Back to top]
NO-NSAIDs: From Inflammatory Mediators to Clinical
Readouts
Stefano Fiorucci and Elisabetta Antonelli
Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase
(COX)-2 selective inhibitors (COXIBs) are widely used drugs.
However, their use is hampered by gastrointestinal, cardiovascular
and renal side effects. Nitric oxide (NO)-releasing NSAIDs,
NO-NSAID, are a new class of anti-inflammatory and analgesic
drugs generated by adding a nitroxybutyl or a nitrosothiol
moiety to the parent NSAID via a short-chain ester
linkage. While efficacy of nitrosothiol-NSAIDs still awaits
investigation, nitroxybutyl-NO-NSAIDs have been extensively
studied in humans. The combination of balanced inhibition
of the two main COX isoforms with release of NO confers to
NO-NSAIDs reduced gastrointestinal and cardiorenal toxicity.
It is suggested that the NO, which is released as the compounds
are broken down, may counteract the consequences of the NSAID-induced
decrease in gastric mucosal prostaglandins. Recent clinical
trials with NO-NSAIDs have provided data consistent with pre-clinical
observations.
[Back to top]
Nitric Oxide, Aspirin-Triggered Lipoxins and NO-Aspirin
in Gastric Protection
John L. Wallace
The use of nonsteroidal anti-inflammatory drugs is associated
with an incidence of severe gastrointestinal adverse events
of 2-4%, the most common of which is bleeding. These events
are largely attributable to the ability of these drugs to
suppress prostaglandin and thromboxane synthesis. Prostaglandins
perform a number of important functions in the gastrointestinal
tract, particularly with respect to resistance of the mucosa
to injury. Nitric oxide also appears to be a key mediator
of gastrointestinal mucosal defence, and this has been exploited
in the development of a novel class of anti-inflammatory drugs,
called “NO-NSAIDs”, which exhibit little if any
gastrointestinal toxicity. NO-NSAIDs are more effective than
traditional NSAIDs in reducing pain and inflammation. Another
class of inflammatory mediators that contribute to gastrointestinal
mucosal defence are the lipoxins. These products of arachidonic
acid metabolism can increase the resistance of the stomach
to the damaging effects of aspirin. Indeed, aspirin can trigger
the formation of a lipoxin by the stomach which acts to diminish
the damaging effects of this drug. Lipoxins and nitric oxide
are important mediators of mucosal defence in the stomach
(and elsewhere in the gastrointestinal tract) and represent
attractive therapeutic targets for reducing the incidence
of gastric ulceration.
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