The role of nonsedating antihistamines in asthma therapy.

There is well-established evidence that histamine plays a significant role as a chemical mediator in asthma. However, although antihistamines are commonly used for the treatment of allergic rhinitis, their use in asthma has been somewhat controversial. Mechanistically, their application for asthma appears logical. In addition to their effects at the histamine receptor, antihistamines, in a dose-dependent fashion, inhibit the release of preformed mediators such as histamine and mediators synthesized de novo including the metabolities of arachidonic acid from mast cells and basophils. Antihistamines also show, in a concentration-dependent manner, anti-inflammatory and immunomodulatory activity through their effects on epithelial cells, endothelial cells, macrophages, eosinophils, and T lymphocytes. Clinically, there appears to be a link between allergic rhinitis and asthma such that treatment of the upper airway has been shown to benefit lower airway disease. Of interest is that although antihistamines have been shown to reduce asthma symptoms and improve quality of life, generally, they have not, at doses sufficient to control rhinitis, improved objective measures of lung function. This could potentially be achieved, in a fashion similar to that observed in concentration-dependent in vitro studies, by using higher medication levels. However, most antihistamines, both first- and second-generation, cannot be used above recommended doses without causing unacceptable side effects including sedation and psychomotor function impairment. As newer antihistamines with improved therapeutic indices have been developed, asthma studies can and must be conducted to evaluate high-dose therapy with the potential of reaping the anti-inflammatory and immunomodulatory effects of these drugs.     

Antiinflammatory effects of oxatomide.

There is increasing evidence that histamine may have wider proinflammatory and immunomodulatory activities than previously reported. It may influence several functions of lymphocytes, monocytes, basophils and macrophages, modulating the release of inflammatory mediators and cytokines. These observations have aroused interest in the pharmacology and clinical applications of histamine H1 receptor antagonists and have led to the identification of novel antiinflammatory properties for this class of drugs. Oxatomide, initially characterized as an H1 antagonist, inhibits the secretion of several mediators of inflammation from human basophils and mast cells. In vitro oxatomide inhibits the release of both preformed (histamine and tryptase) and de novo synthesized mediators (leukotriene C4 and prostaglandin D2). The inhibitory effect is not restricted to basophils and mast cells but is also evident on other inflammatory cells such as the neutrophils. In this cell, oxatomide inhibits arachidonic acid mobilization, and leukotriene B4 and platelet-activating factor synthesis, presumably by reducing the activity of cytosolic phospholipase A2. These observations extend the pharmacological activities of oxatomide beyond H1 receptor antagonism and suggest that this drug influences a variety of biochemical events in human inflammatory cells. These antiinflammatory activities help to explain its beneficial effect in various allergic and inflammatory disorders, including urticaria, allergic rhinitis and bronchial asthma.     

New Insights into the Roles for Basophils in Acute and Chronic Allergy

Basophils represent less than 1% of peripheral blood leukocytes. They are often recruited to the site of allergic inflammation, albeit in small numbers. However, it remained uncertain whether basophils play any significant role in allergic reactions or act as minor and redundant 'circulating mast cells'. We have recently demonstrated that basophils play critical roles in systemic anaphylaxis and chronic allergic inflammation, distinctively from mast cells. Basophils are one of the major players in the IgG-but not IgE-mediated systemic anaphylaxis, in contrast to mast cells. In response to the allergen-IgG immune complexes, basophils release the platelet-activating factor rather than histamine as the major chemical mediator to induce the systemic anaphylaxis. The depletion of basophils protects mice from death due to anaphylactic shock. Basophils also play a crucial role in the development of the IgE-mediated chronic allergic inflammation with massive eosinophil infiltration in the skin, independently of T cells and mast cells, even though basophils account for only ~ 2% of the infiltrates. The basophil depletion shows a therapeutic effect on on-going allergic inflammation. Accumulating evidence suggests that basophils function as initiators rather than effectors of the chronic allergic inflammation. Thus, basophils and their products seem to be promising therapeutic targets for allergic disorders.     

Second-generation antihistamines in asthma therapy: is there a protective effect?

Second-generation histamine H(1) receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and antileukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.     

Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.     

Efficacy of Second-Generation Antihistamines in Patients with Allergic Rhinitis and Comorbid Asthma

Background and aims. Allergic rhinitis (AR) and asthma share common mediators, cytokines, and chemokines from mast cells and basophils that are central to the complex cascade of events involved in the inflammatory response. Histamine is the salient mediator released after immunologic challenge, initiating multiple pathologic processes of the allergic reaction that result in bronchial smooth muscle contraction, vasodilation, mucus hypersecretion, and edema. The recent identification of a fourth histamine receptor has reinforced clinical interest in the pleiotropic effects of histamine and the relative roles of histamine receptors in mediating immune and inflammatory responses. Material and methods. A comprehensive literature search was conducted for the following terms, alone or in combination: allergic rhinitis, asthma, antihistamines, histamine, and histamine receptors, and for the second-generation antihistamines azelastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, and rupatadine. Clinical trials were included that reported results for patients with AR and comorbid asthma who were treated with second-generation antihistamines. The search dates ranged from 1995 through 2010. Clinical studies that were not placebo controlled or double blinded were excluded from this review. Results. A total of 14 clinical trials of second-generation nonsedating antihistamines were included in this review. Conclusion. H1-antihistamines have been shown to attenuate the symptoms associated with early- and late-phase allergic reactions. Cumulative clinical evidence indicates that H1-antihistamines may have a beneficial effect on asthma symptoms and improve quality of life. Scientific significance. Mechanistic and clinical data suggest that the potential of H1-antihistamines to alleviate comorbid asthma symptoms in AR patients should be further investigated.     

Toll-like receptors in the respiratory system: Their roles in inflammation

Allergic airway inflammation develops in the context of innate immune cells that express Toll-like receptors (TLRs). TLRs recognize microbial components and evoke diverse responses in immune and other respiratory cells through distinct signaling pathways. Bacterial and viral infection in the airway modulates the extent of allergic inflammation. TLR stimulation controls T helper (Th) 1, Th2, and Th17 cell differentiation, cytokine production in mast cells, and activation of eosinophils via direct and indirect pathways. TLR signals in dendritic cells increase expression of major histocompatibility complex proteins and T-cell coreceptors, resulting in greater T-cell activation with Th1 bias. TLR signals in mast cells increase their release of IL-5, and TLR signals in airway epithelial cells enhance airway generation of proallergic cytokines. Although these responses play an important protective role in infection, they may exacerbate allergic inflammation. Under some conditions, TLR stimulation, especially via TLR9, reduces Th2-dependent allergic inflammation through induction of Th1 responses. Therefore, understanding the regulatory role of TLRs in the pathogenesis of allergic airway inflammation may shed light on improving inflammation control in asthmatic patients.     

Second-Generation Antihistamines in Asthma Therapy

Second-generation histamine H₁ receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and anti-leukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.     

Anaphylaktoide Reaktionen in der Prähospitalphase

The term anaphylactoid reaction is a generic term used for allergic reactions with symptoms of anaphylaxis. Anaphylaxis is a severe systemic allergic reaction that is potentially fatal. It requires prompt recognition and immediate management. The syndrome can affect virtually any organ in the body, although reactions involving the respiratory, the cardiovascular, the cutaneous and the gastrointestinal systems are most common. Anaphylaxis is caused by the release of mediators from mast cells and basophiles. Reactions typically follow a uniphasic course; however, 20% will be biphasic in nature. The second phase usually occurs after an asymptomatic period of 10 hours in the mean.Adrenaline is the pharmacological treatment of choice and should be used in all patients showing signs of beginning blood pressure decrease or upper airway oedema. Further therapy in the treatment of anaphylaxis includes circulatory support, volume therapy, antihistamines and corticosteroids. Post-treatment observation of these patients is absolutely necessary. Once recovered, patients should be hospitalized and monitored for the following 24-48 hours.     

Pathophysiology of ocular allergy: The roles of conjunctival mast cells and epithelial cells

Allergic eye disease is associated with IgE-mediated conjunctival inflammation leading to signs of immediate hypersensitivity, including redness, itching, and tearing. Pathologic studies using conjunctival mast cells demonstrate that these cells, when sensitized with IgE antibody and exposed to environmental allergens, release mediators involved with allergic inflammation. The type, release kinetics, and concentration of these mediators in the conjunctiva have not been completely characterized. The ability to isolate and purify mast cells and epithelial cells from human conjunctival tissue has permitted the study of mediator release and cell-to-cell signaling in this tissue. Our laboratory has developed in vitro and in vivo models to better understand how inflammatory cells are recruited to and infiltrate conjunctival tissues. These models demonstrate that mast-cell activation may supply sufficient cytokine signaling to initiate and direct the well-orchestrated trafficking of eosinophils to the ocular surface, facilitate their adhesion, and cause release of potent mediators of ocular inflammation.     

Conjunctival mast cells in ocular allergic disease.

Allergic eye disease is a common clinical problem adversely affecting the quality of life for millions of sufferers. This ocular process is associated with IgE-mediated conjunctival inflammation leading to signs of immediate hypersensitivity including redness, itching, and tearing. Pathologic studies have shown that the conjunctiva contains mast cells that when sensitized with IgE antibody and exposed to environmental allergens can release mediators of allergic inflammation. The type, release kinetics, and concentration of these mediators in the conjunctiva have not been completely characterized. The ability to isolate and purify mast cells and epithelial cells from human conjunctival tissue has permitted the study of mediator release and cell-to-cell signaling in this tissue. Our laboratory has developed in vitro and in vivo models to better understand how inflammatory cells are recruited to and infiltrate conjunctival tissues. These models demonstrate that mast cell activation may supply sufficient cytokine signaling to initiate and direct the well-orchestrated trafficking of eosinophils to the ocular surface, facilitate their adhesion, and cause release of potent mediators of ocular inflammation.     

New approaches to allergen immunotherapy

Allergic diseases are common problems affecting 20% to 30% of the US population. Mast cells and basophils are the primary effector cells mediating allergic inflammation through the triggering of membrane immunoglobulin E receptors (FcεRI) with antigen. Allergen immunotherapy is used as one treatment for allergic disease and results in the inhibition of mast cell and basophil responses through unknown mechanisms. In this review, we examine potential mechanisms that could result in blunted human mast cell/basophil functional responses, strategies aimed at using these mechanisms to develop new immunologically based therapies, and recent findings that have broad implications toward our understanding of how mast cells/basophils become desensitized.     

Dexamethasone does not inhibit the release of mediators from human mast cells residing in airway, intestine, or skin

Glucocorticoids are potent anti-inflammatory drugs that are widely used in the treatment of allergic disorders. Their actions are often species specific or cell-type specific. Previous studies have demonstrated that glucocorticoids inhibit mediator release from mast cells derived from the peritoneum of mouse or rat and from guinea pig lung, but not those residing in human lung parenchymal tissue. In the present study, we have analyzed the effect of overnight culture with dexamethasone (10(-6) to 10(-7)M) on the subsequent IgE-dependent release of mediators from human mast cells derived from airway tissue, intestine, and skin. Airway tissue was passively sensitized with antigen-specific, IgE-rich serum during the culture period and subsequently challenged with ragweed antigen E. Skin and intestinal mast cells were challenged with anti-IgE. Histamine and immunoreactive LTC4 and PGD2 release was monitored in all experiments. Prostaglandin E release was quantitated in the experiments using airway tissue. Dexamethasone treatment failed to inhibit the release of mast cell mediators from all three tissues, but it inhibited the antigen-induced release of immunoreactive PGE from other cells residing in airway tissue. These results confirm earlier studies of the effects of glucocorticoids on human lung parenchymal mast cells, but contrast with the inhibitory effects of steroids observed in murine mast cells and human basophils.     

Effets synergiques et additifs entre les différentes classes d'anti-inflammatoires de l'asthme

Persistent asthma is a chronic airway inflammatory disease that requires treatment with anti-inflammatory drugs. Inhaled corticosteroids are the cornerstone of the treatment of airway inflammation. Clinical studies have shown that asthmatic patients treated with long-acting β₂-agonists and inhaled corticosteroids have more reduced exacerbations than those given higher doses of corticosteroids suggesting synergistic effects on the inflammatory process. The understanding of the molecular modes of action of these two classes of drugs explained part of the enhanced anti-inflammatory activity of the combination therapy. However, the production of cysteinyl-leukotrienes is not well controlled by corticosteroids. Antileukotrienes, by the blockade of the effects of cysteinyl-leukotrienes, exert therefore a complementary antiinflammatory action. In addition, the efficacy of antileukotrienes for the symptomatic treatment of allergic seasonal rhinitis can improve both the quality of life and asthma control in mild to moderate persistent asthmatic patients, with seasonal allergic rhinitis, who are already treated with an antileukotriene as maintenance treatment for their asthma.     

The role of mast cells in asthma

Mast cells store or generate a number of substances, such as histamine, leukotrienes, specific chemotactic factors, and proteases, which have potent inflammatory effects. Mast cells are present in mammalian lung in the bronchial wall, in the epithelium itself, and in airway lumens. Evidence implicating mast cells in the induction of airway muscle constriction and mucosal inflammation includes direct studies of mast cell secretion, measurement of histamine release, and inhibition of asthmatic reactions with antihistamines and with the inhibitor of mast cell degranulation, sodium cromoglycate. Definitive evaluation of the role of the mast cell in asthma remains elusive, in part because of the general hyperactivity of airway smooth muscle in asthmatics.     

Etiopathogenesis and Management of Perennial Allergic Rhinitis

Perennial allergic rhinitis is an inflammatory disorder characterized by symptoms of nasal congestion, rhinorrhea, sneezing, and itching. The prevalence of allergic rhinitis is quite common and affects 20% or more of various populations. Some patients with allergic rhinitis are symptomatic only during the pollen season, while many others are allergic to multiple allergens including indoor allergens such as house dust mites, animal dander, cockroaches, and fungi, which lead to perennial symptoms. Immunoglobulin (Ig)-E is the proximate cause of perennial allergic rhinitis. Circulating IgE antibodies bind to the high affinity IgE receptor on mast cells and basophils. IgE antibodies, bound to the receptors crosslinked by allergen, initiate the secretion of inflammatory mediators including histamine, leukotrienes, and cytokines. These mediators can induce both acute and chronic changes that result in symptoms of allergy. Many therapies are approved for the treatment of allergic rhinitis including intranasal corticosteroids, antihistamines with or without decongestants, and nasal cromolyn sodium (sodium cromoglicate). Allergen avoidance is the mainstay of therapy for many patients but is not always practical. For those patients who have not responded to appropriate medications, allergen specific immunotherapy may also be effective.A number of studies with omalizumab have shown that it is effective in the treatment of seasonal allergic rhinitis induced by pollen such as ragweed and birch pollen. Omalizumab is a molecularly cloned humanized monoclonal antibody inhibiting human IgE. It binds specifically to the region of the IgE molecule that binds to the IgE receptor on the mast cell or basophils. Because omalizumab cannot bind IgE molecules that are already bound to the surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab does not appear to stimulate an immune response against itself. It rapidly reduces free serum IgE levels by over 95% when administered at therapeutic doses and also results in the reduction of IgE receptors on mast cells and basophils. The combined effects of reduction of both free IgE in serum and the receptor density on the mast cells or basophils results in decreased allergen-stimulated mediator release. Preliminary studies in the treatment of perennial allergic rhinitis supports omalizumab's efficacy and safety. The compound has been well tolerated. Aside from urticarial reactions, adverse effects appear to be minimal. Omalizumab is the first of several new immune-based specifically targeted molecules that may prove to be extremely valuable in the treatment of perennial allergic rhinitis, as it is often unresponsive to traditional therapies.     

The re-emergence of the mast cell as a pivotal cell in asthma pathogenesis

Asthma is characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation. Mast cells have long been thought to play a central role in asthma through their ability to release proinflammatory mediators, but this role has been questioned by the lack of efficacy of antihistamines and so-called mast cell-stabilizing drugs. Recent comparisons between the immunopathology of asthma and eosinophilic bronchitis have led to the re-emergence of the mast cell as a pivotal cell in asthma. Eosinophilic bronchitis is a condition in which patients present with chronic cough, and shares many of the inflammatory features associated with asthma, but without variable airflow obstruction or airway hyperresponsiveness. The only striking pathologic difference between these conditions is that, in asthma, the airway smooth muscle is infiltrated by mast cells. This suggests that interactions between mast cells and airway smooth muscle cells are critical for the development of the disordered airway physiology in asthma.     

The role of mast cells in allergic inflammation

The histochemical characteristics of human basophils and tissue mast cells were described over a century ago by Paul Ehrlich. When mast cells are activated by an allergen that binds to serum IgE attached to their Fc?RI receptors, they release cytokines, eicosanoids and their secretory granules. Mast cells are now thought to exert critical proinflammatory functions, as well as potential immunoregulatory roles, in various immune disorders through the release of mediators such as histamine, leukotrienes, cytokines chemokines, and neutral proteases (chymase and tryptase). The aim of this review is to describe the role of mast cells in allergic inflammation. Mast cells interact directly with bacteria and appear to play a vital role in host defense against pathogens. Drugs, such as glucocorticoids, cyclosporine and cromolyn have been shown to have inhibitory effects on mast cell degranulation and mediator release. This review shows that mast cells play an active role in such diverse diseases as asthma, rhinitis, middle ear infection, and pulmonary fibrosis. In conclusion, mast cells may not only contribute to the chronic airway inflammatory response, remodeling and symptomatology, but they may also have a central role in the initiation of the allergic immune response, that is providing signals inducing IgE synthesis by B-lymphocytes and inducing Th2 lymphocyte differentiation.     

Biology of basophils and their role in allergic inflammation

Chronic allergic inflammatory reactions involve the infiltration and participation of many different cell types. Although it has been evident for many years that tissue specific mast cells have a primary role in the early stages of these reactions, recent studies indicated that, in addition to mast cells response, a later reaction which selectively recruits the circulating lymphocytes, eosinophils and basophils to the site of inflammation, is the hallmark for the progression of allergic diseases.     

Roles of IL-18 in basophils and mast cells.

Basophils and mast cells are effecter cells in allergen/IgE-mediated immune responses. They induce type 1 immediate immune response in airway or other organ, resulting in bronchial asthma and other allergic diseases. However, they also play a critical role in host defense against infection with helminthes. Upon linkage of FcepsilonRI with a complex of allergen and IgE, basophils and mast cells release a large amount of Th2 cytokines and chemical mediators. Therefore these responses are "acquired allergic responses" and induce allergic diseases, such as bronchial asthma. However, basophils and mast cells derived from cultured bone marrow cells with IL-3 for 10 days express IL-18Ralpha chain and produce Th2 cytokines in response to the stimulation with IL-3 and IL-18 without FcepsilonRI cross-linkage. Furthermore, they produce Th2 cytokines upon stimulation with several TLR ligands, such as LPS. This finding may suggest the presence of allergen/IgE-independent allergic responses, which we would like to designate as "innate allergic response". However, in vivo treatment with IL-18 and IL-2 protects against gastrointestinal nematode infection by activating intestinal mucosal mast cells in STAT6-independent manner, suggesting the importance of innate allergic response against helminth infection. Here we discuss the functional role of IL-18-induced "innate allergic response" in disease and host defense.