Proteoglycans in Inflammation Pp-89-102
M.
Delehedde, F. Allain, S.J. Payne, R. Borgo, C. Vanpouille, D.G. Fernig and E.
Deudon
Inhibitors of Endocannabinoid Degradation as Potential Therapeutic Agents Pp-103-113
M.
Maccarrone, M. van der Stelt, G.A. Veldink and A. Finazzi-Agrò
5-Lipoxygenase in the Central Nervous System: Therapeutic Implications Pp-115-121
H. Manev
and T. Uz
Chemokines and Receptors as Targets in Anti-Inflammatory Therapy Pp-123-130
M.
Galindo and J.L. Pablos
Macrolides as Immunomodulatory Agents Pp-131-141
P.C.Y.
Woo, S.K.P. Lau and Kwok-yung Yuen
Novel Approaches for Allergy Pp-143-156
H.T. Zafra and M.C. Zacharisen
[Back to top] Proteoglycans in Inflammation
M.
Delehedde, F. Allain, S.J. Payne, R. Borgo, C. Vanpouille, D.G. Fernig and E.
Deudon
Proteoglycans
(PG) consist of a core protein and an associated glycosaminoglycan (GAG) chain
and reside on the cell surface and in the extracellular matrix. The different
GAG chains of PG, heparan sulfate/heparin (HS), dermatan/chondroitin sulfate,
keratan sulfate and of hyaluronic acid, which is not associated with a core
protein, are synthesized as polymers of repeating disaccharide units. However,
the structures of GAG chains are highly diverse. For example, the
post-polymerisation modification of heparan chains (a polymer of glucuronic
acid b1-4 N-acetyl glucosamine) by the
sulfation of specific residues and the epimerisation of glucuronate to
iduronate generates HS, which has a potential sequence complexity greater than
that of the human proteome. Although only a fraction of this chemical
complexity is used, it provides the framework for GAG chains to interact with a
vast repertoire of proteins, with a specificity that is as high as required. As
a consequence of their multiple interactions, PG are intimately involved in the
different stages of inflammation, from the recruitment of inflammatory cells to
the release of mediators of inflammation by infiltrating leukocytes and the
turnover of extracellular matrix. The overarching theme of PG in inflammation
is the regulation of the inflammatory microenvironment, which must change
continuously and dynamically during the progression of the inflammatory
response as observed in various pathologies such as arthritis and asthma. These
changes include the modulation of the activity of GAG-binding cytokines, growth
factors, proteases and protease inhibitors. The interactions of these
regulatory proteins with GAG provides much of the focus for GAG-based
therapeutic targets.
[Back to top] Inhibitors of Endocannabinoid Degradation as Potential Therapeutic Agents
M. Maccarrone,
M. van der Stelt, G.A. Veldink and A. Finazzi-Agrò
Endocannabinoids
are amides, esters and ethers of long chain polyunsaturated fatty acids, which
include anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol
(2-AG) as the main endogenous agonists of cannabinoid (CB) receptors. The
biological actions of these compounds at CB receptors depend on their life span
in the extracellular space, which for AEA is regulated by intracellular uptake
through a selective AEA membrane transporter (AMT), followed by intracellular
degradation by an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH).
Together with AEA and 2-AG and their synthetic enzymes, CB receptors, AMT and
FAAH form the “endocannabinoid system”. Here, we review recent literature on
the properties of the constituents of this system, and on its role in
inflammation. We also show how restraining the flexibility of the acyl chain of
AEA affects the ability of this compound to bind to CB receptors and to
interact with AMT and FAAH. Furthermore, we show how molecular dynamics
simulations with free and restrained AEA and a number of its analogs, generated
by lipoxygenase-mediated hydroperoxidation, help to understand the structural
requirements essential for the interaction with the proteins of the
endocannabinoid system. The hydroxy AEAs described herein might act in vivo as
inhibitors of endocannabinoid metabolism, the only ones of natural origin as
yet known. The relevance of these findings, which help to predict and facilitate
the design of novel drugs with greater potency and/or selectivity at the
different molecular targets of AEA, will be discussed in the light of their
therapeutic potential.
[Back to top] 5-Lipoxygenase in the Central Nervous System: Therapeutic Implications
H. Manev
and T. Uz
5-Lipoxygenase
(5-LOX) is a protein with catalytic activity that is essential for transforming
arachidonic acid into leukotrienes and that has the ability to bind and
possibly affect the function of a number of cellular proteins, including
cytoskeletal proteins. A limited number of clinically-used drugs target the
5-LOX pathway; they are either 5-LOX inhibitors or antagonists of leukotriene
receptors and are primarily used for the treatment of asthma. 5-LOX is also
expressed and enzymatically active in various compartments of the mammalian
brain, including central nervous system (CNS) neurons. However, insufficient
information is available on the extent to which 5-LOX-related drugs cross the
blood-brain barrier. Research into the CNS 5-LOX pathway indicates that 5-LOX
may participate in a number of brain pathologies, including developmental
neurometabolic diseases, stroke, seizures, Alzheimer’s disease,
aging-associated neurodegeneration, prion disease, multiple sclerosis, and
brain tumors. Physiologically, 5-LOX appears to be involved in neurogenesis.
The expression of 5-LOX is affected by hormones and appears to be subject to
epigenetic regulation via alterations in DNA methylation in the region of the 5-LOX
promoter. In this review, we propose that a novel 5-LOX drug therapy could be
targeted not only to 5-LOX enzymatic activity and leukotrienes, but also toward
modifying 5-LOX expression and the possibility of interfering with
non-enzymatic actions of 5-LOX proteins. It is suggested that a new 5- LOX
pharmacopoeia, which would be effective in the CNS would significantly advance
research on the role of 5-LOX in the brain.
[Back to top] Chemokines and Receptors as Targets in Anti-Inflammatory Therapy
M.
Galindo and J.L. Pablos
An essential feature of different inflammatory conditions, such as infective, autoimmune, allergic or vascular diseases, is the recruitment of infiltrating leukocytes. A large number of chemoattractant cytokines termed chemokines appear as critical factors in the development of inflammatory cell infiltration by interacting with specific receptors on leukocytes and regulating leukocyte movements. Chemokines may also play important roles in many other leukocyte functions such as differentiation of effector phenotypes or cell growth.
A limitation to understand the participation of chemokines in chronic inflammatory diseases and to the development of chemokine based therapy is redundancy and overlapping receptor-ligand profiles of this system. However, emerging evidences point to specific roles for individual chemokines or chemokine receptors in many chronic inflammatory disorders such as glomerulonephritis, multiple sclerosis, rheumatoid arthritis, atherosclerosis and lung and airway inflammatory diseases. Genetic deletion of chemokines or their receptors have confirmed a relevant role for these factors in murine models of inflammation.
A
variety of common drugs used to treat human inflammatory disease, including
those inhibiting NF-kB activation, have
indirect effects on chemokines expression. More potent and specific strategies
for inhibition of different chemokines or their receptors are being developed.
Neutralizing antibodies or a variety of peptides or small molecules have
demonstrated their potential to target leukocyte infiltration in different
animal models and provide the basis for their use to treat human inflammatory
diseases.
[Back to top] Macrolides as Immunomodulatory Agents
P.C.Y.
Woo, S.K.P. Lau and Kwok-yung Yuen
Macrolides,
an old class of antibiotics, have attracted intense interest in recent years because
of their diverse non-antibiotic properties. Among these properties, their
immunomodulating effects were most extensively examined. In this review, their
broad range of effects on the immune system as shown by various in-vitro,
ex-vivo, and in-vivo experiments and clinical studies were discussed. It is now
evident that various macrolides can modulate the innate immune system, with
greater effects from 14- and 15-membered than the 16-membered derivatives.
Although results from in-vitro studies appear to depend on the use of
individual drugs and experimental conditions, they provide clues to the
mechanisms of modulating different pathways of the immune system. On the other
hand, animal and clinical studies, which summarize the effects of individual pathways,
concluded that many macrolides are useful in a wide variety of clinical
situations, from treatment of inflammatory lung diseases to application in
transplantation. As for adaptive immunity, limited data were available but
attenuation by macrolides was also reported in preliminary studies. Owing to
their diverse effects on the immune system and inconclusive results from
different in-vitro studies, the mechanism of their immunomodulation is not yet
fully understood and correlation of effects with chemical structures is not
conclusive at the moment. It may be more valuable for future studies to
concentrate on the genetic basis for mechanisms on one hand, and additional
areas of clinical applications on the other.
[Back to top] Novel Approaches for Allergy
H.T.
Zafra and M.C. Zacharisen
The inflammation associated with allergic disease is complex and still not completely understood. With the identification of the various cells and mediators involved in the inflammatory response, new therapies have been and are being developed for use.
The central effector cell in allergic inflammation is termed the TH2 helper cell, a member of the subset CD4+ Tlymphocytes, which secrete specific cytokines such as IL-4, IL-5, IL-9 and IL-13. These cytokines promote mast cell differentiation and IgE production, and also promote eosinophil growth, maturation, migration and activation. In contrast, TH1 helper lymphocytes secrete IFN-g (interferon- g), and stimulate phagocyte-dependent cell-mediated immunity. TH1 cells can downregulate TH2 cells, primarily through the effects of IFN-g.
Controlling allergic disease focuses on blocking mediators and down-regulating pro-inflammatory cytokines and inflammatory cells stimulated by the allergic TH2 response. Antihistamines are receptor antagonists for the primary mediator histamine released during the early allergic response. Currently, glucocorticosteroids are the mainstay of anti-inflammatory therapy because of their ability to inhibit the production of inflammatory cytokines. Much has been
accomplished in creating newer forms of topical steroids with more potent anti-inflammatory effects and reduced side effects.
The
main focus of research is on developing therapeutic strategies which target
different pathways to modify the allergic inflammatory response. For example,
leukotriene modifiers are a relatively new class of anti-inflammatory
medications that block the products of arachidonic acid metabolism. The use of
recombinant humanized monoclonal antibody directed against IgE to neutralize
and eliminate free circulating IgE is showing success in clinical trials. In
development are monoclonal antibodies directed against various inflammatory
cytokines such as IL-4 and IL-5, and a recombinant human receptor for IL-4.
Another focus is to administer IL-12 in an attempt to inhibit the TH2 response
and promote a TH1 immune response. There are strategies for modifying
immunotherapy to improve immunogenicity and improve TH1 immune response. All of
these novel concepts are examples of tremendous strides that have made in the
development of anti-allergy therapy.