Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 2, Issue 3, 2003

The review focuses on the application of macrobiomolecules and their derivatives that are capable of inhibiting ocular inflammatory and allergic responses. With a better understanding of molecular pathways of immunoregulation and the various factors involved in inflammation, and the concurrent development of modern technology, many macrobiomolecules have been utilized as immunomodulators. Ocular applications of macrobiomolecules have not been reviewed previously. Macrobiomolecules including compounds with peptide structure, compounds with nuclear acid and modified lipids have been successfully applied in the treatment of experimental and clinical ophthalmic diseases. These macrobiomolecules fall into categories, comprising: a) compounds with peptide structure, such as antiflammins and derivatives, antithrombins, and melanocyte-stimulating hormone (MSH); b) compounds with nucleic acid structure, such as immunostimulatory DNA sequences, antisense oligonucleotides, and ribonucleic acid; c) lipid compounds and their derivatives, such as fish oil, prostaglandin, ricinoleic acid, and oxidized lipid products; and d) other macrobiomolecules, including heparin and propolis. Antiflammins are an example of synthetic peptides with sequence homology to uteroglobulin that inhibit phospholipase A2. Topical administration of antiflammin suppresses acute ocular inflammation in experimental endotoxin-induced uveitis (EIU) and inhibited allergic responses in murine allergic conjunctivitis. Another example of macrobiomolecules that have immune stimulatory effects are the CpG-containing antisense oligonucleotides, also known as immunostimulatory oligonucleotides (ISS) or CpG motifs. CpG motifs enhance host responses against bacterial infection and have been exploited as a novel therapy to treat cancer, allergy and asthma. ISS also inhibits on-going Th2 response and induces a de novo Th1 response in murine allergic conjunctivitis. Additional macrobiomolecules, i.e., oxidized phospholipids, are recently reported to inhibit endotoxin-induced, or interleukin-1& bgr;- induced, NFkB-mediated upregulation of inflammatory genes. These chemically synthesized phospholipids block the interactions among endotoxin, endotoxin-binding protein and CD14, resulting in the inhibition of inflammation induced by endotoxin. In conclusion, macrobiomolecules are potentially desirable therapeutic medications for ocular allergy and inflammation.

Allergic immune responses result from complex cascades of events mediated by multiple effector cells and their signaling molecules. The multiplicity of mediators involved in allergic reactions also provides numerous potential targets for intervention. In recent years, a number of approaches have been undertaken to inhibit the synthesis and function of allergen-specific IgE antibodies, induce blocking anti-allergen IgG antibodies, prevent the differentiation of Th2 cells, or eliminate the cells or mediators causing allergic symptoms. Directed molecular evolution using DNA shuffling and appropriate screening technologies provides a means to generate improved vaccines and therapeutics with the potential for short-term and long-term therapeutic effects. DNA shuffling enables the generation of large libraries of chimeric genes from which improved variants can be selected based on functional properties. Structural information obtained from shuffled molecules will also help in the understanding of receptor-ligand interactions and may assist in the design of small molecules that specifically interact with given targets. Here we review strategies to generate novel allergy vaccines and anti-allergic therapeutics, with particular emphasis on approaches utilizing directed molecular evolution.

The urokinase receptor (uPAR) is an important part of the plasminogen activation system. Urokinase-type plasminogen activator (uPA) was the first identified ligand of uPAR. Therefore, the major role of uPAR was thought to be in the regulation of pericellular proteolysis through the activation of plasminogen into active plasmin. However, recent studies have shown that uPA binding to uPAR plays a pivotal role in signaling functions that influence cell behaviour. Newly identified ligands, vitronectin and high molecular kinin-free kininogen, suggest tha t uPA R also has adhe sive and a nti-a dhesive pr operties. In a ddition, being a glycosyl-phospha tidylinositol (GPI)-anchored protein, uPAR can interact laterally with a wide variety of membrane proteins including integrins, endocytic receptors, caveolin, the gp130 cytokine receptor, the EGF receptor, and FPRL1 a classical chemoattractant receptor. These interactions underline the importance of uPAR, despite its lack of an intracellular domain, in many cell events including adhesion, migration, growth and gene expression. More importantly, the role of uPAR in adhesion, extravasation, chemotaxis of leukocytes, and tissue repair explains its involvement in the early and late events of the inflammatory reaction. Thus, emerges the concept that uPAR is at the centre of an integrative signaling network with proand anti-inflammatory attributes that may lead to the identification of new therapeutic targets. We propose to classify uPAR into a new group of membrane proteins having a chemokine-like function and to name this new class MACKINE (Membrane-Anchored ChemoKINE-like proteins).

FK506, renamed tacrolimus, is an immunosuppressive agent used in organ transplants to prevent allograft rejection and graft-versus-host disease. FK506 binds to an immunophilin, FK506-binding protein-12 (FKBP-12), and the resulting complexes inactivate calcineurin, a pivotal protein enzyme in T cell receptor signaling. FK506 in known to induce immunosuppression due to calcineurin inhibition / interruption of the NF-AT pathway of T lymphocytes, recent studies suggest that it has additional anti-inflammatory properties. For instance, FK506 has shown efficacy in the treatment of refractory rheumatoid arthritis, a chronic inflammatory disease. Apoptosis, a form of programmed cellular suicide, may provide a key function in establishing tissue homeostasis, as well as self-tolerance, through eliminating autoreactive immunocompetent cells. In our study, we have demonstrated that FK506 augments steroid-induced T cell apoptosis. Furthermore, FK506 enhances superantigen-induced T cell apoptosis by downregulation of the survival gene, Bcl-XL. The observed potentially apoptotic of FK506 may act as an anti-inflammatory agent by preventing activation of immune system. FK506 also has an additional effect on the glucocorticoid receptor (GR) and its signal transduction. After entry into the cell, FK506 binds to FKBP-52, one of the FK506-binding proteins associated with the GR complex. When cells are exposed to glucocorticoids, steroids bind to the GR and release it from the complex. Free GRs transmigrate into the nucleus where they may interact with transcriptional factors, such as nuclear factor-kB(NF-kB), an important regulator of inflammatory responses. Through binding to FKBP-52 in the GR complex, FK506 may facilitate the nuclear transmigration of GR, which would augment the anti-inflammatory effect of steroids. This paper presents the antiinflammatory potential of FK506 and therapeutic strategies to prevent inflammation using this agent.

Hydrophilic 2,3-dihydro-5-hydroxy-2-benzofuranacetic acids were designed to maximize the antioxidants potency of phenols and are also chemically related to α-tocopherol. Besides quenching free radicals and blocking the chain breaking reaction, these compounds may act as modulators of the inflammatory cascade triggered by oxidative stress. In fact they block the activation of Nuclear Factor Kappa B (NF-kB) induced by okadaik acid, H2O2, phorbol ester, ceramide and LPS. In addition, in vivo they reduce the inflammatory response reaction and display a marked protection in hemorrhagic shock, septic shock, and myocardial ischemia-reperfusion injury. The persistence of the inflammatory phase has detrimental consequences for the process of wound repair. Increased lipid peroxidation has been shown to play an important role in the wound healing disorders of diabetes: indeed it may prolong the inflammatory phase and significantly alter the mechanisms of angiogenesis. Hydrophilic dual vitamin E-like antioxidants have the capacity to modulate the inflammatory phase and to improve the altered angiogenesis therefore suggesting a possible role in the management of diabetic foot ulcer.

Many chronic debilitating diseases result from uncontrolled inflammation. Inflammatory cells, such as neutrophils, eosinophils, basophils, mast cells, macrophages, endothelial cells, and platelets, respond to inflammatory stimuli and foreign substances by producing bioactive mediators, such as eicosanoids, chemokines, and cytokines. These mediators act as autocrines and paracrines by interacting with many cell types to amplify the inflammatory response. Studies of lipoxins, eicosanoids derived from the lipoxygenase pathways, provide evidence of endogenous antiinflammatory molecules to dampen the inflammatory response. This article reviews the recent advances in antiinflammatory research and provides insight into pharmaceutical and clinical relevance. Selective cyclooxygenase 2 inhibitors have currently been in the spotlight for their anti-inflammatory effects without the side effects of older, nonselective non-steroidal anti-inflammatory drugs. However, many new areas of interest in the regulation of the inflammatory response include leukotriene receptor antagonists, monoclonal antibodies to cytokines, and synthetic analogs of lipoxins.

Histamine H1 receptor antagonists comprise the largest class of medications used in the treatment of allergic disorders, especially asthma, rhinitis and urticaria. They are administered for their ability to produce blockade of histamine action at H1 receptors. Age, race, gender, body-weight, hepatic and renal function influenced the pharmacokinetics of H1 antagonist. During the last years, the second generation of histamine H1 receptor antagonists has been developed to reduce or eliminate the sedation and the anticholinergic adverse effects that occur with older antihistamines. Several synthetized antihistamine drugs have been studied in allergic rhinitis, asthma, urticaria and dermatitis. All second-generation H1 antagonists offer a superior clinical profile compared with the older antihistamines. All the new drugs have good clinical efficacy. The overall pathogenic view of respiratory allergy has profoundly changed and evolved over the past ten years. Particular attention has been paid to the relationship between rhinitis and asthma and between the upper and lower respiratory airways. According to the operative definition of allergic rhinobronchitis or, as recently proposed, of united airways disease (UAD). The increase in knowledge of the mechanisms of allergic inflammation in the respiratory tract has partly clarified the pathophysiology of allergic and non-allergic diseases that can involve nose, bronchi and skin. The concept of UAD has also relevant diagnostic and therapeutic implications. The more recent antihistamine medications may have an important role in controlling the inflammation induced by allergic stimuli affecting all airways.