Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 2, Issue 1, 2003

Opioid peptides are found to be released from cells of the immune system during inflammation and stress, and are associated with altered immune responses. Moreover, concentrations of opioid peptides are increased in peripheral blood and at the sites of inflammatory reactions. Inflammatory responses to infection in vivo are initiated by directed migration of phagocytes, neutrophils and macrophages in peripheral tissue, and microglia in the brain, into the sites of infection. The migration follows in phagocytosis of the invading microorganisms and killing by generation of reactive oxygen species such as superoxide anion. Endomorphins 1 and 2 are recently isolated endogenous opioid peptides, and potent and selective high affinity μ-opioid receptor agonists. First, we have examined effects of endomorphins 1 and 2 on chemotaxis, phagocytosis and superoxide anion production in phagocytes. Endomorphins 1 and 2 potentiated chemotaxis in neutrophils, whereas they inhibited chemotaxis in macrophages and microglia. In addition, both endomorphins blocked phagocytosis of Escherichia coli by microglia, without affecting that by neutrophils and macrophages. Moreover, endomorphins 1 and 2 blocked the production of superoxide anion by neutrophils and macrophages, whereas they potentiated that by microglia. The next attempt was to examine effects of endomorphins 1 and 2 on particular functions of each phagocyte. Endomorphins 1 and 2 inhibited neutrophil adhesion, whereas they potentiated macrophage adhesion. Moreover, both endomorphins significantly delayed constitutive neutrophil apoptosis via phosphoinositide 3-kinase pathway. In contrast, endomorphins 1 and 2 inhibited tumor necrosis factor-α, interleukin (IL)-10 and IL-12 productions, but potentiated IL-1β production by macrophages. Therefore, endomorphins may differentially modulate the immune functions in neutrophils, macrophages and microglia.

It is now a well-acknowledged fact that lung airway and tissue inflammation is a major aspect of the pathobiology of pulmonary diseases such as asthma, emphysema, adult respiratory distress syndrome, cystic fibrosis and interstitial lung diseases. Asthma incidence is increasing and standard therapies show significant flaw. Although steroid therapy plays a major role in the treatment of asthma, it suffers from a number of side-effects. Currently, new approaches directed toward the treatment of inflammation associated with pulmonary diseases have included the development of agents which have impact on T-lymphocytes, mast cells, macrophages, neutrophils and eosinophils. These cells have the ability to produce some inflammatory mediators (e.g. cytokines, leukotrienes and cyclooxygenase products) or to release degradative enzymes, toxic proteins and toxic oxygen metabolites. It has also been demonstrated that leukotrienes play an important role in the pathogenesis of asthma. Leukotriene receptor antagonists and 5-lipoxygenase and 5-lipoxygenaseactivating protein (FLAP) inhibitors are likely to be the most significant new anti-asthma drugs.This review will deal with new approaches for asthma therapy as well as discuss new anti-asthma drugs.

Tachykinins constitute a family of neuropeptides which share the common C-terminal sequence Phe-Xaa-Gly- Leu-Met-NH2. This sequence is critical for their interaction with specific receptors and for producing most of their biological effects. Tachykinins are widely distributed in the peripheral nervous system of the respiratory, urinary and gastrointestinal tract, stored in enteric neurons and in peripheral nerve endings of capsaicin sensitive primary afferent neurons from which they are released by stimuli having physiological as well as pathological relevance. The most studied effects produced by tachykinins in these systems are smooth muscle contraction, plasma protein extravasation, mucus secretion, and recruitment and activation of immune and inflammatory cells. In recent studies using experimental animal models, tachykinins have been shown to play an important role in several inflammatory conditions, such as airway inflammation and asthma, allergic contact dermatitis, arthritis, cystitis, inflammatory bowel disease, trinitrobenzenesulfonic acid -induced colitis, Clostridium difficile toxin A-induced-enteritis, and acute pancreatitis. The use of tachykinin receptor antagonists and gene-knockout animals has enabled identification of the role of tachykinins and their receptors in different disease conditions. The evidence obtained using animal models suggests that tachykinins could contribute to inflammation in various human diseases and points to the potential usefulness of tachykinin receptor antagonists as therapeutic targets.

Chronic renal diseases with enhanced glomerular protein filtration are accompanied by tubulointerstitial inflammation and progression to renal function deterioration. Filtered protein, like albumin, is a pathogenic factor per se in the progression of renal diseases. The nuclear factor κB (NF-κB), a ubiquitous transcription factor, mediates the expression of numerous inflammatory or fibrotic mediators such as RANTES, MCP-1, TNF-α, cytokine receptors, or iNOS in renal as well as in other tissues. It is evident that NF-κB is involved in protein-overload stimulated renal inflammatory mechanisms. This paper reviews the recent studies concerning NF-κB-activation and expression inducing renal inflammation and fibrosis in several proteinuric animal experimental models as well as protein-induced NF-κBmediated renal inflammatory signal transduction pathways in vitro, with a special focus on albumin-endocytosis in proximal tubular cells. Protein-induced NF-κB-activation and NF-κB-mediated signal transduction pathways seem to be interesting therapeutic targets in proteinuric renal diseases. Therefore, this paper shows recent pharmaceutical approaches to inhibit renal NF-κB-activity.

Glucocorticoid (GC) exhibits immunosuppressive and anti-inflammatory effects by suppressing the nuclear factor functions on T cells and monocytes / macrophages. GC exerts its effects by binding cytosolic GC receptor (GR) and antagonizes the transcription factors including AP-1, NF-κB and STATs, in both transcriptional regulation and upstream cross-talk with signaling molecules, resulting in the inhibition of target gene expression such as cytokines and other proteins, followed by the suppression of T cell activation and the production of inflammatory mediators. In addition, in anti-allergic actions of GC, one of the most important targets is mast cell. GC specifically inhibits the release of chemical mediators from mast cells. It also suppresses survival and activation of mast cells, at least in partial, overlapping with the suppressive mechanisms of T cell activation and monocytes / macrophages functions, by inhibiting the production of growth factors and inflammatory mediators, and suppressing the transcriptional induction of Th2-type cytokines, such as IL-4, -5, -10, -13 and TNF-α, chemokines and adhesion molecules, resulting in the suppression of immediate- and late-phase of allergic inflammation and remodeling. In this issue, we summarize the molecular mechanisms of GC to regulate the transcription factors, molecules regulated by GC and its action on the immune system in contrast with other agents, and also discuss the specific molecular targets of a possible drug design for allergy learned from the variable immunosuppressive and anti-inflammatory actions of GC.

Nuclear factor (NF)-κB is a transcription factor associated with modulation of the immune response. NF-κB is a heterodimer consisting of subunits p50, p52 and p65 (Rel A) or Rel B or cRel (the most common NF-κB heterodimer consist of subunits p50 and p65) that belong to the Rel family of genes, which includes the v-rel oncogene, the c-rel protooncogene and dorsal, a Drosophia morphogen. In its quiesecent state, NF-κB is in the cytoplasm, bound to a family of inhibitory proteins that are collectively called IkB. Several molecules, including interleukin (IL)-1, lipopolysaccharide (LPS), tumor necrosis factor (TNF)-α, reactive oxygen intermediates and viral products activate NF-κB through phosphorylation and subsequent degradation of IkB. Activation by these agents leads to exposure of the nuclear localization signal of NF-κB and entry into the nucleus. Once in the nucleus, NF-κB transcriptionally activates a variety of genes involved in the inflammatory process, including intracellular adhesion molecule (ICAM)-1, vascular cellular adhesion molecule (VCAM)-1, endothelial leukocyte adhesion molecule (ELAM) and IL-8. The family of NF-κB transcription factor is a topic of interest in the biomedical community stemming from the role NF-κB plays in almost every aspect of cell regulation such as stress responses, immune cell activation, apoptosis, proliferation, differentiation and oncogenic transformation. Recently, we have developed a novel molecular strategy termed the decoy approach to inhibit NF-κB activity. Moreover, E2F decoy strategy has already been used in the clinical trials to prevent the vascular disease. Taken together, the decoy strategy is considered to have the potential of clinical application.

Progress in the management of allergic diseases including asthma, pollen diseases and atopic dermatitis has recently improved patients' quality of life. In addition to steroids, which are powerful inhibitors of allergic inflammation, other anti-allergic compounds, humanized anti-IgE antibody and cytokine modulators have been developed. However, the world-wide prevalence of allergic diseases has been increased during the last two decades, making early intervention to prevent the development of such diseases essential. Through analysis of the clinical evaluation of one kind of traditional remedy in patients with atopic dermatitis, flavonoids were shown to possess significant anti-allergic activity. Among the twenty kinds of flavonoids examined, fisetin, luteolin, apigenin, quercetin and kaempferol inhibited not only the release of chemical mediators but also the production of T-helper (Th)-2 type cytokines (Interleukin (IL)-4, IL-5 and IL-13) by basophils. These flavonoids inhibit expression of these cytokines through their inhibitory effect on the activation of several calcium-calmodulin dependent kinases. Administration of either persimmon leaf extract, which is rich in flavonoids, or its major ingredient astragalin (a glycoside of kaempferol), in atopic dermatitis-model mice (NC / Nga) prevented the onset of dermatitis and showed a substantial ameliorative effect even in mice with open dermatitis. Moreover, a double-blind, randomized, placebo-controlled trial of flavonoid in patients with atopic dermatitis showed a significant effect. These results indicate the possibility that flavonoids, which are contained in vegetables, fruits and tea, may constitute a complementary and alternative medicine for allergic patients and may act as a prophylactic substance against the development of allergic diseases.

Interleukin-8 (CXCL8) belongs to the CXC branch of chemokine family and is primarily involved in the directed migration and functional activation of polymorphonuclear neutrophil leukocytes (PMNs). CXCL8 achieves its cellular effects by direct interaction with cell surface receptors (CXCR1 and CXCR2).CXCL8 is supposed to play a pivotal role in the pathology of several inflammatory diseases and this makes CXCL8 and its receptors attractive therapeutic targets.The first aim of this review is to discuss the potential pathophysiological role of CXCL8 in different pathologies, such as ischaemia / reperfusion injury, psoriasis, cystic fibrosis, and cutaneous melanoma.CXCL8 inhibitors, including a monoclonal neutralizing antibody of CXCL8, and small organic molecules which selectively inhibit CXCL8 receptor binding, will be reviewed. Finally, the ability of some non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit CXCL8-induced PMN chemotaxis will also be discussed.