Novel
and Alternative Non-Steroidal Treatments for Asthmatic Inflammation
Guest
Editor: Mario Cazzola
Glycosaminoglycans and the Regulation of Allergic
Inflammation Pp.221-225
Mark J. Rose and Clive
Page
Anti-IgE Monoclonal Antibody (Omalizumab) in the
Treatment of Atopic Asthma and Allergic Respiratory Diseases Pp.227-229
Gennaro D’Amato,
Gennaro Liccardi, Paolo Noschese, Antonello Salzillo, Maria D’Amato and Mario
Cazzola
The Potential of PDE4 Inhibitors in Respiratory Disease
Pp.231-236
Domenico Spina
Potential Role of Antibiotics in the Treatment of Asthma Pp.237-242
Francesco Blasi,
Roberto Cosentini, Paolo Tarsia and Luigi Allegra
Targeting Th2 Cells in Asthmatic Airways Pp.243-255
Gaetano Caramori,
Kazuhiro Ito and Ian M. Adcock
Chemokine
Receptor Inhibitors as a Novel Option in Treatment of Asthma Pp.257-261
Ian M. Adcock and
Gaetano Caramori
Cytokine-Directed
Therapy in Asthma Pp.263-269
Masakazu Ichinose and
Peter J. Barnes
Anti-Inflammatory
Activities of b2-Agonists
Pp.271-277
Nicola A. Hanania and
Robert H. Moore
Chemokines
and Chemokine Receptors: Potential Therapeutic Targets in Multiple Sclerosis Pp.279-290
Diane M. Muller,
Michael P. Pender and Judith M. Greer
Endotoxin
Recognition Molecules MD-2 and Toll-like Receptor 4 as Potential Targets for Therapeutic
Intervention of Endotoxin Shock Pp.291-297
Kensuke Miyake
Peripheral
and Central Mechanisms of Inflammatory Pain, with Emphasis on MAP Kinases Pp.299-303
Ru-Rong Ji
Dendritic
Cell-Based Therapies in the Bench and the Bedsides Pp.305-310
Sk. Md. Fazle Akbar,
Hidehiro Murakami, Norio Horiike and Morikazu Onji
Melanocortin
Receptor Type 3 as a Potential Target for Anti-Inflammatory Therapy Pp.311-315
Connie W. Lam and
Stephen J. Getting
Molecular
Therapeutic Targets in Inflammation: Cyclooxygenase and NF-κB Pp.317-324
Teresa Krakauer
Cytokine
and Nitric Oxide Production Following Severe Envenomation Pp.325-332
Vera L. Petricevich
Abstracts
[Back to top] Glycosaminoglycans
and the Regulation of Allergic Inflammation
Mark J. Rose and Clive
Page
Glycosaminoglycans (GAGs) are large, polyanionic molecules expressed throughout the body. The GAG heparin, co-released with histamine, is synthesised by and stored exclusively in mast cells, whereas the closely related molecule heparan sulphate is expressed, as part of a proteoglycan, on cell surfaces and throughout tissue matrices. These molecules are increasingly thought to play a role in regulation of the inflammatory response and heparin like molecules are now being seriously considered to hold potential in the treatment of inflammatory diseases such as asthma. Heparin and related molecules have been found to exert anti-inflammatory effects in a wide range of in vitro assays, animal models and in human disease. The anti-inflammatory activities of heparin are independent of the well-established anticoagulant activity of heparin, suggesting that the separation of these properties could yield novel anti-inflammatory drugs, which may be useful in the future treatment of inflammatory diseases.
[Back to top] Anti-IgE Monoclonal Antibody (Omalizumab) in the
Treatment of Atopic Asthma and Allergic Respiratory Diseases
Gennaro D’Amato,
Gennaro Liccardi, Paolo Noschese, Antonello Salzillo, Maria D’Amato and Mario
Cazzola
Since the discovery of immunoglobulin E (IgE) antibodies thirty-six years ago, our understanding of the mechanisms of allergy has improved to such an extent that we can now better differentiate allergy from non-allergic hypersensitivity, and allergic/atopic from intrinsic/nonatopic bronchial asthma.
IgE antibodies are crucial immune mediators of airway inflammation in allergic atopic asthma and IgE-mediated hypersensitivity reactions are the likely mechanisms of allergen-induced airway obstruction. In addition, IgE may cause chronic airway inflammation in asthma through effector cells activated via high-affinity (FcεRI) or low-affinity (FcεRII) IgE receptors. Therapeutic anti-IgE antibodies able to reduce free IgE levels and to block the binding of IgE to FcεRI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (rhuMAb-E25; omalizumab) binds IgE at the same site as these antibodies bind FcεRI and FcεRII. As a consequence, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells
and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the FcεR1 receptor already masks the anti-IgE epitope.
Studies in patients with atopic asthma demonstrated that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted to be able to reduce asthma-related symptoms, to decrease corticosteroid use and to improve quality of life of asthmatic patients.The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis and food allergies), a favourable side-effect profile and a twice-monthly dosing frequency.
[Back
to top] The Potential of PDE4 Inhibitors in Respiratory Disease
Domenico Spina
Glucocorticosteroids remain the gold standard therapy for the prophylactic treatment of asthma. Concerns regarding its long-term use particularly in young children has provided an impetus for discovering novel anti-inflammatory molecules with high tolerability and clinical efficacy. Whilst for chronic obstructive pulmonary disease (COPD), there exist no pharmacological treatment for the prevention of decline in lung function. Targeting phosphodiesterase (PDE)4 is one example of this approach and inhibitors of this enzyme are the most advanced drug class in the respiratory pipeline. A number of potent PDE4 inhibitors have undergone clinical trials with moderate success. Tolerability and clinical efficacy issues have dampened enthusiasm in this area. However, with the prospect of newer potent and side effect free inhibitors on the horizon give this area guarded optimism. This review will summarise the most recent information concerning the effectiveness of PDE4 inhibitors as novel anti-inflammatory agents for the treatment of respiratory diseases.
[Back to top] Potential Role of Antibiotics in the Treatment of Asthma
Francesco Blasi,
Roberto Cosentini, Paolo Tarsia and Luigi Allegra
Although the role of antibiotic treatment in asthma is still disputed, clinical use of antimicrobials in this setting is more widespread than warranted on the basis of indications in the literature. Viral upper respiratory tract infections are known to be involved in asthma exacerbations. More recently, evidence of Mycoplasma pneumoniae and Chlamydia pneumoniae involvement in asthma attacks has been reported both in adult and paediatric populations. These pathogens are also involved in chronic asthma, and both in vitro and animal model studies indicate that atypical agents may play a role in the pathogenesis of the disease. Recent studies on asthma patients with evidence of atypical infection suggest that specific antimicrobial treatment (basically macrolides or fluoroquinolones) may confer additional advantages compared to standard therapy alone. Furthermore, a considerable amount of data has been gathered describing additional effects associated with macrolide treatment (reduced bronchial hyper-responsiveness, altered cytokine production, etc.). These non-antimicrobial effects have been defined as “anti-inflammatory activity”. Should this information be confirmed, the use of macrolides in patients with asthma may be twofold: eradication of occult atypical infection; and reduction in the airway inflammation burden. Future lines of research in this field should attempt to determine whether specific antibiotic treatment may alter the natural history of asthma.
[Back to top] Targeting
Th2 Cells in Asthmatic Airways
Gaetano Caramori,
Kazuhiro Ito and Ian M. Adcock
The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and –resistant asthma still represents a great clinical burden accounting for ~50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroidsparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible individuals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease.
[Back
to top] Chemokine Receptor Inhibitors as
a Novel Option in Treatment of Asthma
Ian M. Adcock and Gaetano Caramori
The migration of cells towards and into the site of an inflammatory insult is critical for maintenance of the inflammatory response and its resolution. This is particularly so in the case of asthma where recruitment of key effector cells may control disease severity, responsiveness to current therapies and the airway remodelling associated with the disease. Chemokine receptor antagonists have the hope of preventing inflammatory cell recruitment to the airway and perhaps as a consequence affect the resolution of airway remodelling. A number of selective antagonists directed at various CC and CXC receptors thought to be important in asthma are currently at various stages of clinical development. Results from these studies will determine whether chemokine receptor antagonists will prove beneficial in severe glucocorticoiddependent and –resistant asthmatic subjects. Furthermore, it is possible that early treatment with these agents may prevent the disease from becoming established.
[Back
to top] Cytokine-Directed Therapy in
Asthma
Masakazu Ichinose and Peter J. Barnes
Increasing evidence of the pathological roles of multiple cytokines in orchestrating and perpetuating inflammation in asthma has prompted the evaluation of novel anti-cytokine therapies. Anti-IL-5 antibody markedly reduces peripheral blood and airway eosinophils, but does not appear to be effective in symptomatic asthma. Inhibition of IL-4, despite promising early results in asthma has been discontinued and blocking IL-13 might be more effective. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, as systemic delivery produces side effects. Inhibition of TNF-a may be useful in severe asthma. Agents that target IL-13 are still early in the development process. Many chemokines are involved in the inflammatory response of asthma and several small molecule inhibitors of chemokine receptors are in development. CCR3 antagonists, which block eosinophil chemotaxis, are in clinical development for asthma therapy. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side effects with these non-specific inhibitors may be reduced by the inhaled route.
[Back
to top] Anti-Inflammatory Activities of b2-Agonists
Nicola A. Hanania and Robert H. Moore
Beta2-adrenergic agonists ( β2-agonists) play a pivotal role in the acute and chronic management of asthma. Their major action on the airways is the relaxation of smooth muscle cells. In addition to their bronchodilator properties, β2-agonists may have other effects through their activation of β2-receptors expressed on resident airway cells such as epithelial cells and mast cells and circulating inflammatory cells such as eosinophils and neutrophils. These non-bronchodilator activities of β2-agonists may enhance their efficacy in the management of asthma. In pre-clinical studies, the anti-inflammatory effects of β2-agonists are demonstrated through their stabilizing effect on mast cells and their inhibition of mediator release from eosinophils, macrophages T-lymphocytes, and neutrophils. In addition, β2-agonists may inhibit plasma exudation in the airway, the release of neuropeptides from sensory nerves, and mediator release from epithelial cells. These in vitro observations are not as clearly demonstrated in clinical trials, which may be explained by the rapid desensitization of β2-adrenergic receptors on airway inflammatory cells. The regular use of short-acting β2-agonists alone has been shown to have deleterious effects on asthma control. Therefore, short-acting agents should only be used when needed for rescue of acute symptoms. Monotherapy with long-acting β2-agonists has also been associated with poor asthma control. However, when given concomitantly with inhaled corticosteroids, β2-agonists may potentiate the anti-inflammatory effect of corticosteroids, improve asthma control and prevent exacerbations.
[Back
to top] Chemokines and Chemokine
Receptors: Potential Therapeutic Targets in Multiple Sclerosis
Diane M. Muller, Michael P. Pender and Judith M. Greer
Multiple sclerosis (MS) is a common inflammatory and demyelinating disease of the central nervous system (CNS), which causes progressive neurological disability. The disease is characterised pathologically by destruction of the myelin sheaths, which surround nerve fibres in the CNS. It is believed that this tissue damage in the brain and spinal cord of MS patients is caused by an inflammatory response that is initiated when autoreactive T cells, specific for myelin antigens, cross the blood-brain barrier and detect their antigen within the CNS. As a result, most therapies to date have been immunosuppressive and/or anti-inflammatory in nature, targeting the processes involved in activation and migration of leukocytes and promotion of the immune response. Over the last decade, a family of chemotactic cytokines called chemokines, have been found to be involved in the trafficking of leukocytes in both the normal and pathological states. The expression of these chemokines and their receptors is increased during the acute phase of MS and also in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). As a result, these chemokines have become an emerging focus for research into novel therapeutics for EAE and ultimately MS. This review will briefly describe the structure and function of chemokines and their receptors, before discussing the latest advances in developing pharmacological agents to block the effects of chemokines involved in promoting the inflammatory response in EAE and MS.
[Back
to top] Endotoxin Recognition Molecules MD-2 and Toll-like
Receptor 4 as Potential Targets for Therapeutic Intervention of Endotoxin Shock
Kensuke Miyake
Gram-negative sepsis is the major cause of deaths in intensive care units of hospitals and continues to increase worldwide due to the increased frequency of invasive procedures and therapy leading to immunosuppression. This syndrome is characterized by endothelial damage, coagulopathy, loss of vascular tone, tissue hypoperfusion, and multiple-organ failure. They are caused by uncontrolled, overwhelming inflammatory responses, which are triggered by microbial products. Amongst these products, endotoxin also called LPS (lipopolysaccharide), a constituent of the outer membrane of Gram-negative bacteria, is known to play a central role by eliciting immune responses leading to production of proinflammatory cytokines. Our understanding of LPS recognition has increased dramatically over the last several years by identification of Toll-like receptor 4 (TLR4) and MD-2 as LPS recognition molecules. TLR4 is a mammalian homologue of drosophila Toll. The extracellular domain of TLR4 is associated with a molecule called MD-2. Mice lacking either TLR4 or MD-2 do not respond to LPS and are resistant to endotoxin shock. Here, the potential for TLR4-MD-2 as target molecules for therapeutic intervention is discussed.
[Back
to top] Peripheral and Central Mechanisms of Inflammatory
Pain, with Emphasis on MAP Kinases
Ru-Rong Ji
Tissue injury is associated with inflammation and produces inflammatory pain. In animal models, inflammatory pain is normally produced by injection of irritative chemicals into the hindpaw or joint of animal. Inflammatory pain manifests as an expression of neuronal plasticity, which consists of peripheral sensitization (increased sensitivity of primary sensory neurons in the peripheral nervous system, PNS) and central sensitization (increased sensitivity of spinal dorsal horn and other neurons in the central nervous system, CNS). Activation of several protein kinases causes both forms of sensitization via posttranslational, translational, and transcriptional regulation. In particular, mitogen-activated protein kinase (MAPK), such as ERK and p38, is activated by inflammatory mediators in primary sensory and secondary order dorsal horn neurons and participates in the generation and maintenance of inflammatory pain. Development of specific MAPK inhibitors will open a new avenue to the pharmacological intervention of inflammatory pain.
[Back
to top] Dendritic Cell-Based Therapies in the Bench and the
Bedsides
Sk. Md. Fazle Akbar, Hidehiro Murakami, Norio Horiike and Morikazu Onji
Antigen-presenting dendritic cells (DCs) represent trace population of leukocytes that are widely distributed over the whole body. DCs are regarded as inducer of antigen-specific adaptive immune responses. However, various types of functions of DCs are now exposing. In the steady-state, DCs induce immunogenic tolerance to self antigens and harmless entities and thus maintain normal homeostasis. On the other hand, in presence of non-self and dangerous entities, DCs play a cardinal role in the induction of innate immunity by producing type-1 interferons. DCs are also essential for the development of antigen-specific B-lymphocytes and plasma cells. Infection, depletion and dysfunction of DCs have been reported from patients with chronic microbial infections. Impaired functions of DCs have also been shown from patients with autoimmune diseases and allergic diseases. Patients with cancers also have phenotypic and functional impairment of DCs
These observations inspired optimism of using DC-based therapy for treating different pathological conditions. DC-based therapies showed excellent therapeutic potential in animal model of human diseases. The efficacy of DC-based therapy has not been properly evaluated in patients with different diseases. However, some clinical trials indicate that administration of antigen-pulsed DCs might be safe and possibly effective.
In this review, we would first provide a description about the nature and functions of DCs that have been taught from the laboratory benches. Next, we would discuss how the information taught in the laboratory benches has been applied in patient’s bedsides.
[Back
to top] Melanocortin Receptor Type 3 as a Potential Target
for Anti-Inflammatory Therapy
Connie W. Lam and Stephen J. Getting
Alpha-melanocyte stimulating hormone (a-MSH) and other melanocortin peptides are potent anti-inflammatory agents exhibiting efficacy in many animal models of acute and chronic inflammation. They are derived from a larger precursor molecule known as the POMC prohormone and are produced both centrally and peripherally. They exert their effect by binding to melanocortin receptors, of which five have been cloned and partially characterised. Agonism at these receptors leads to adenylate cyclase activation and subsequent increases in cAMP formation. Two receptors to date have been proposed to mediate the actions of the melanocortin peptides in an inflammatory scenario, the MC1 and 3-R, and here we discuss our findings proposing the MC3-R as a novel therapeutic target. The potential anti-inflammatory role for MC3-R is in its infancy, however, recent studies have shown that melanocortin peptides are effective in mice bearing a non-functional MC1-R (recessive yellow e/e mice). This ability to inhibit cell migration appears to be via inhibition in cytokine and adhesion molecule expression and is due to their abilities to interfere with cell signalling pathways. Identification of endogenous mediators of anti-inflammation, their receptors and the pathologies they are effective in, is of benefit to the medical community, and will hopefully have reduced side effects. We believe that specific small molecule agonists directed at MC3-R could be potential novel therapeutics for inflammatory conditions.
[Back
to top] Molecular Therapeutic Targets in Inflammation:
Cyclooxygenase and NF-κB
Teresa Krakauer
Inflammation is the host response to infection and injury. Inflammatory cells respond to foreign substances and inflammatory stimulus by producing bioactive mediators such as prostanoids, cytokines and chemokines. These mediators have complex, pleiotropic effects and interact with many cell types to amplify the inflammatory response. Dysregulation of these processes can lead to acute and chronic inflammatory diseases and pharmacological intervention is necessary to attenuate cellular inflammation pathways. Cyclooxygenase-2, the key inducible enzyme responsible for producing prostanoids, and the nuclear factor–kappa B (NF-κB) activation pathway, which regulates the transcription of inflammatory genes, represent attractive targets for developing anti-inflammatory therapeutics, as both pathways are activated by diverse inflammatory stimuli. This article reviews recent advances in anti-inflammatory drug development in both of these areas. Selective inhibitors of inflammation including cyclooxygenase inhibitors, antibodies against inflammatory cytokines, cytokine receptor antagonist, antibodies against adhesion molecules and therapeutics directed against the NF-κB activation pathway will be discussed.
[Back
to top] Cytokine and Nitric Oxide Production Following Severe
Envenomation
Vera L. Petricevich
Venom is a complex mixture of many substances such as toxins, enzymes, growth factor activators, and inhibitors are particularly responsible for the deleterious effects of cells. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Envenomation by bees, scorpions, snakes, spiders and wasps involves the activation of the inflammatory response with the release and activation of pro-inflammatory cytokines and other mediators, such as nitric oxide. Recently, a battery of cytokines produced by activated T cells or macrophages have been added to in envenomations. Cytokines are important for the interactions between cells in the immune and inflammatory responses. Although the pathophysiology of envenomation is not fully understood, venom and immune responses are known to trigger the release of cytokines and nitric oxide. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and, as well as a host of physiologic events such as activation of vasodilation, hypotension and increased nitric oxide production. Accumulating evidence indicates that these cytokines play important roles in mediating cell recruitment and activation necessary for inflammation and the repair of tissue damage. A better understanding of the involvement of the inflammatory system in different envenoming syndromes may have future therapeutic benefits.