Current Medicinal Chemistry- Anti- Inflammatory & Anti- Allergy Agents, Vol. 2, No. 2, 2003
Contents
Cyclopentenone Prostaglandins as Anti-Inflammatory
Agents: A Novel Therapeutic Strategy?
Pp. 85-93
A. Ianaro , P. Maffia , M. Di Rosa and A. Ialenti
Modulation of Interleukin-10 Production by Therapeutic
Drugs Pp. 95-106
Bernard Royer , Jean-Pierre Kantelip and Michel Arock
New Approaches for the Treatment of Allergic Conditions Pp. 107-118
Csaba Rusznak
Strategies for Leukotriene Modulation in Dermatology:
Current Evidence and Visionary Perspectives Pp. 119-130
Giovanni Luigi Capella
Mitogen-Activated Protein Kinases: New Molecular Targets
for Pharmacological Treatment of Inflammatory Lung Diseases Pp. 131-141
G. Pelaia , G. Cuda , A. Vatrella , D. Fratto , P.
Tagliaferri , R. Maselli , F.S. Costanzo
and S.A. Marsico
From Hygiene Hypothesis to Novel Allergic Asthma
Therapeutics Pp. 143-155
I. Sayers , G. Le Gros and J.L. Harper
Role of Peripheral Tachykinin Receptors in Neurogenic
Inflammation of the Respiratory, Genitourinary and Gastrointestinal
Systems Pp. 157-174
Stefano Evangelista , Riccardo Patacchini and Carlo Alberto Maggi
Chemokines as Therapeutic Targets for Renal Diseases Pp. 175-190
Takashi Wada , Kouji Matsushima and Hitoshi Yokoyama
Pharmacological Targets for the Inhibition of Neurogenic
Inflammation Pp. 191-218
Zsuzsanna Helyes , Erika Pinter , Jozsef Nemeth and Janos Szolcsanyi
[Back to top] Cyclopentenone
Prostaglandins as Anti-Inflammatory Agents: A Novel Therapeutic Strategy?
A. Ianaro , P. Maffia , M. Di
Rosa and A. Ialenti
Cyclopentenone prostaglandins (cyPG) are naturally occurring derivatives of prostaglandin E1, E2, and D2 containing an a,b-unsaturated carbonyl group in the cyclopentane ring structure (cyclopentenone). These molecules exhibit a wide array of biological activities, including anti-inflammatory effects, by interacting with intracellular target proteins. A large body of evidence shows that cyPG mainly interact with signal proteins and transcription factors, such as “Nuclear Factor-kB” (NF-kB), “Heat Shock Factor-1” (HSF1), and Peroxisome Proliferator Activated Receptor-g (PPAR- g), which play crucial and opposite roles in inflammatory diseases.
NF-kB is an early mediator of immune and inflammatory responses whereas HSF1, and PPAR-g activation have been related to mechanisms leading to the resolution of inflammation.
The identification of cyclopentenone as the active moiety of cyPG responsible for HSF1 activation as well as for the inhibition of inflammatory genes in human cells, opens new perspectives for the design and development of a new class of cytoprotective molecules devoid of the pleiotropic effects of natural eicosanoids.
In this review we summarize the recent information on the anti-inflammatory effect of cyclopentenones and discuss the possible development of novel therapeutic strategies relying upon the simultaneous activation of cytoprotective genes and down-regulation of inflammatory genes.
[Back to top] Modulation
of Interleukin-10 Production by Therapeutic Drugs
Bernard Royer , Jean-Pierre Kantelip and Michel Arock
Interleukin-10 (IL-10) is a cytokine with now well established immunomodulatory activity in both physiological and pathological processes. Its particular secretion pathway, i.e., a spontaneous production that increases after activation in many cell types, strengthens its regulatory role. Various drugs can interfere with the production of IL- 10, explaining, in part, their mechanism of action. This paper gives an overview of the effect of several major drugs on the production of IL-10 by various cell populations.
Among glucocorticoids, dexamethasone is probably the most studied, and generally shows an inhibitory effect on the production of IL-10 in vitro. However, its effect depends on the type of stimulus and on its concentration, explaining probably some discrepant results reported in the literature. Interestingly, used in vivo, dexamethasone increased the plasmatic concentration of IL-10. Similar effects have been observed with methylprednisolone or hydrocortisone, as several clinical trials reported that these molecules induced an increase in IL-10 levels while, when used in vitro , these drugs led to a decrease in the production of IL-10. The other immunosuppressive drugs, such as tacrolimus or cyclosporin, inhibited the production of IL-10 by T- or B-lymphocytes. This effect seemed to be focused on these cells, that are the main targets of these drugs. This might explain why other models, such as peripheral blood mononuclear cells or whole blood are not sensitive to these drugs. In clinical trials, however, cyclosporin has also led to a decrease in IL-10 level.
As well, the beta-adrenergic family appears to be one of the more interesting concerning its effect on IL-10 secretion. Indeed, epinephrine, norepinephrine, and beta agonists induced an increase in the production of IL-10 both in vitro and in vivo, while beta-blockers had the opposite effect. The use of beta2 selective agonists or antagonists has led to the attribution of such effect to beta2 receptors. The effects of other drugs, such as antihistamines, non-steroidal anti-inflammatory drugs, gold derivatives, aprotinine, heparin, methotrexate, rituximab or OKT3 on the production of IL-10 will also be discussed in this review.
Finally, the effects of various drugs on the production of IL-10 depend on several parameters. For instance, experiments performed in vivo or in vitro have sometimes led to opposite results. Interestingly, some drugs with so-called “wellknown” mechanisms of action have demonstrated more recently an effect on IL-10 secretion. As an example, adrenergic agonists such as epinephrine or beta2-agonists, have been shown to enhance the production of IL-10, an effect probably favorable when these drugs are used in asthma. Thus, some “old and well-known” drugs might in fact act in part through their ability to modulate the production of IL-10 at the local or general level. If such properties could be demonstrated, this could lead to a better knowledge of the mechanisms of the immunomodulatory properties of these drugs and to the design of new molecules targeting such secretions.
[Back to top] New
Approaches for the Treatment of Allergic Conditions
Epidemiological studies clearly demonstrate that the prevalence of allergic diseases has increased, and that the higher diagnosis rates are due not simply to changes in diagnostic fashion or improvements in detection. Additionally, the increasing recognition that allergic rhinitis and allergic asthma frequently co-exist has led to the concept of the “United Airways”, namely that these seemingly separate disorders are manifestations of the same disease expressed in either the upper or the lower airways.
Current asthma management guidelines emphasize the importance of early intervention with inhaled corticosteroids as first-line anti-inflammatory therapy. Several studies have demonstrated that certain second generation of antihistamines possess anti-inflammatory activity. Studies were also conducted investigating their effects in combination with leukotriene receptor antagonists versus intranasal and/or inhaled corticosteroids in both allergic rhinitis and asthma. Amongst the novel anti-cytokine therapies, treatments with anti-IL-5, anti-IL-13, anti-TNF-a, as well as soluble IL-4 receptor antagonists are currently being studied in asthmatics. Monoclonal antibodies against adhesion molecules, as well as T cell-specific peptides are also new and evolving fields of research.
Therapeutic agents inhibiting IgE-mediated responses have also been designed. Of those, a recombinant humanized monoclonal antibody to IgE has been shown to block the biologic effects of IgE.
Allergen immunotherapy (allergy vaccination) is an important therapeutic tool for the management of United Airways Disease and it is indicated in patients with concomitant rhinitis and asthma. Immunotherapy can modify the natural history of the disease and maintains its effects for years after discontinuation.
[Back
to top] Strategies for Leukotriene Modulation in Dermatology: Current
Evidence and Visionary Perspectives
Giovanni Luigi Capella
Leukotrienes (LTs) are a complex family of eicosatetrenoic acid derivatives containing a conjugated triene chain first isolated from leukocytes. The biosynthesis of LTs can be started, or completed, or fully performed at various degrees in several mammal cells including mastocytes, basophils, eosinophils, neutrophils, macrophages, endothelial cells, erythrocytes, and platelets. LTs are potent proinflammatory autacoids: as a whole, their actions include plasma extravasation and induction of edema, leukocyte aggregation, smooth muscle contraction, and polymorphonuclear chemoattraction. Several molecules interfering with the synthesis of LTs mediated by the enzyme 5-lipo-oxygenase or its activating protein (FLAP), or with the binding of LTs to specific receptors have been developed in recent years, mainly for the treatment of bronchial asthma. Three such molecules (LT biosynthesis inhibitor; zileuton; LT receptor antagonists; zafirlukast, and montelukast) are currently marketed worldwide. Owing to the ubiquitous distribution of LTs in the organism, and their involvement in a host of inflammatory disorders, it has become clear that these drugs can be useful in the treatment of many conditions, other than asthma. In the dermatological domain, LT-modulating drugs (either commercially available ones or experimental agents) have been shown to be active or promising in several conditions such as atopic dermatitis, urticaria (chronic idiopathic, pressure delayed, cold- or aspirin-induced), and psoriasis. Further research, clinical, and practical implications, as well as visionary perspectives are surveyed and discussed.
[Back to top] Mitogen-Activated
Protein Kinases: New Molecular Targets for Pharmacological Treatment of
Inflammatory Lung Diseases
G. Pelaia , G. Cuda , A. Vatrella , D. Fratto , P.
Tagliaferri , R. Maselli , F.S. Costanzo
and S.A. Marsico
Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes playing a key role in the transduction of biological signals from cell surface receptors, through the cytoplasm, up to the transcriptional machinery in the nucleus. MAPKs are expressed by alveolar and airway vascular endothelial cells, as well as by bronchial epithelial cells, which actively participate in the inflammatory and immune processes characterizing many lung diseases. We have recently shown, in human pulmonary endothelial cells, that the synthetic glucocorticoid dexamethasone is able to inhibit the phosphorylation-dependent activation of MAPKs induced by oxidative stress and by the pro-inflammatory cytokines interleukin-1b and tumor necrosis factor-a. In primary cultures of human bronchial epithelial cells, our group has also demonstrated that budesonide, a topical corticosteroid widely used as inhaled anti-inflammatory therapy, exerts a potent inhibitory effect on transforming growth factor-b-induced activation of p38, which represents the MAPK subgroup mostly involved in inflammatory processes. Furthermore, other authors have detected an anti-inflammatory action of specific p38 inhibitors in some experimental models of pulmonary inflammation. Therefore, MAPK signalling pathways are emerging as very important, newly recognized targets of anti-inflammatory and immunoregulatory therapies, aimed in particular at controlling the pathogenic events underlying several lung diseases. In this regard, we think that our studies, together with those of other research groups, may contribute to better elucidate the molecular mechanisms responsible for the therapeutic effects of currently available anti-inflammatory agents, as well as to develop novel pharmacological strategies directly targeted at MAPK modulation.
[Back to top] From
Hygiene Hypothesis to Novel Allergic Asthma Therapeutics
I. Sayers , G. Le Gros and J.L. Harper
The prevalence and severity of allergic asthma is increasing worldwide. Epidemiological evidence suggests that the increase in disease prevalence is inversely associated with the occurrence of childhood infections. Specific pathogens, and pathogen-derived components have now been identified that can suppress allergic disease in mice and humans. These discoveries highlight the potential of these microorganisms as a new source of immunotherapeutics. The utility and mechanism of action of these pathogens or pathogen-derived components will be discussed in the context of providing a novel approach for the treatment of allergic airway disease.
[Back to top] Role
of Peripheral Tachykinin Receptors in Neurogenic Inflammation of the Respiratory,
Genitourinary and Gastrointestinal Systems
Stefano Evangelista , Riccardo Patacchini and Carlo Alberto Maggi
A wide distribution of tachykinin-containing projections of capsaicin-sensitive primary afferent neurons is present in the peripheral organs of respiratory, gastrointestinal and genitourinary systems. Tachykinins, along with calcitonin gene-related peptide (CGRP) and other neuropeptides, can be released by adequate stimuli having pathological rather than physiological relevance. In most cases these stimuli are represented by chemical irritants penetrating through the respiratory tree or alimentary channel to the body, or being removed through the urinary system. Tachykinins produce in the visceral organs part of the responses obtained at somatic level by antidromic activation of capsaicin-sensitive nerve terminals and known as "neurogenic inflammation" that is, increase in vascular permeability and plasma protein leakage followed by oedema. In addition tachykinins produce at visceral level smooth muscle contraction, neuronal stimulation, mucus secretion and recruitment/activation of immune cells. The physiological significance of these effects is to afford protection toward chemical irritants or noxious stimuli by facilitating their removal from the body. Nonetheless, a large body of preclinical evidence exists indicating that tachykinins participate in the genesis and/or maintenance of symptoms accompanying various human diseases, such as asthma/bronchial hyperreactivity, cystitis of various aetiologies, inflammatory bowel diseases and irritable bowel syndrome. Tachykinin receptor antagonists, proved capable of preventing/reducing tachykinin-mediated effects in experimental animal models of these pathologies, are expected to afford therapeutically relevant effects in humans.
[Back to top] Chemokines
as Therapeutic Targets for Renal Diseases
Takashi Wada , Kouji Matsushima and Hitoshi Yokoyama
Pathophysiological roles of chemokines, and their cognate receptors have helped elucidating the detailed molecular mechanisms of leukocyte trafficking and activation in inflammatory diseases. Chemokine/chemokine receptor systems might be essential for the pathogenesis of phase-specific renal disorders and the measurement of urinary levels of chemokines might be clinically useful for monitoring different disease phases and activities. In addition, chemokine receptors expressed in renal resident cells may be involved in proliferation, proteinuria, and fibrogenesis as well as chemotaxis. Importantly, the selective intervention of chemokine/chemokine receptor systems (anti-chemokine therapy) may have potential as therapeutic strategies for renal diseases. Despite the apparent redundancy in the chemokine systems, accumulating evidence supports this concept. Small molecule inhibitors of the chemokine/chemokine receptor systems are now being developed. We anticipate that active, orally bio-available inhibitors of chemokines/chemokine receptors for progressive renal diseases as well as other inflammatory disorders will be developed.
[Back to top] Pharmacological
Targets for the Inhibition of Neurogenic Inflammation
Zsuzsanna Helyes , Erika Pinter ,
Jozsef Nemeth and Janos Szolcsanyi
Neuropeptides released from the activated peripheral terminals of capsaicin-sensitive subpopulation of sensory neurons exert local efferent function besides the classical afferent activity. This substantial population of nociceptive afferents expess the capsaicin (vanilloid subtype 1) VR1/ TRPV1 receptor, which is a noxious heat/ proton-gated cation channel. Calcitonin gene-related peptide (CGRP) increases local blood flow by inducing arteriolar vasodilatation, substance P (SP) and neurokinin A cause plasma protein extravasation due to increased microvascular permeability and accumulation of inflammatory cells via neurokinin 1 (NK1) receptors in the innervated area. This set of pathophysiological changes initiated by sensory nerve endings is defined as neurogenic inflammation, which plays significant role in the pathomechanism of numerous diseases like bronchial asthma, allergic rhinitis, conjunctivitis and dermatitis, ekzema, psoriasis, rheumatoid arthritis and migraine. The major problem in the treatment of these conditions is the lack of effective therapy for the neurogenic component of inflammatory processes. Potential ways to inhibit neurogenic inflammation are decreasing the release of inflammatory neuropeptides and / or preventing their effects by receptor antagonists on blood vessels and inflammatory cells. Prejuntional inhibition can be performed by opioid peptides acting mainly on m receptor, nociceptin through opioid receptor like 1 (ORL1/OP4) receptor, histamine via H3 receptor, 5-hydroxytryptamine via 5-HT1B/1D receptor, a2-adrenoceptor agonists, galanine, purine derivatives and somatostatin. According to our results somatostatin released into the circulation from activated sensory nerve terminals exerts systemic anti-inflammatory and analgesic actions. Nitric oxide (NO) has been reported to liberate neuropeptides from sensory nerves, selective inhibitor of inducible NO synthase would also be a possibility to inhibit the release of mediators. Several results suggest that potent synthetic CGRP and NK1 receptor antagonists acting on the target tissues are effective in the management of neurogenic oedema formation. VR1/ TRPV1 receptor is at present a hot topic to develop novel analgesic/ anti-inflammatory drugs acting on the nociceptors. This receptor can be activated by capsaicin, resiniferatoxin, protons, noxious heat, the endocannabinoid anandamide, and lipoxygenase products. Efforts to develop VR1 antagonists are in progress in major drug companies and the promising experimental evidence obtained in our laboratories favours agents acting on somatostatin receptors, which do not mediate endocrine effects. Potential targets on sensory nerve terminals for the development of new anti-inflammatory drugs are summarized in this review with special emphasis on VR1 receptors and somatostatin analogs.