Clinical and Experimental Allergy, 1999, Volume 29, pages 1593–1596
`
`EDITORIAL
`
`Anti-inflammatory actions of new antihistamines
`
`Histamine has been recognized as a major mediator pro-
`ducing allergic reactions and diseases [1]. Antihistamines
`are widely used for treatment of these conditions. First-
`generation antihistamines (traditional antihistamines) includ-
`ing hydroxyzine, chlorpheniramine and diphenhydramine
`display poor selectivity for H1-receptors. They are effective
`in reducing histamine-related symptoms, but the use of them
`have been limited by sedation and troublesome gastro-
`intestinal symptoms due to their penetration of the blood–
`brain barrier and anticholinergic effects,
`respectively.
`Second-generation antihistamines (new antihistamines),
`including terfenadine, feofenadine, cetirizine, ketotifen,
`azelastine and ebastine, which display greater selectivity
`for H1-receptors and lack of penetration of the blood–brain
`barrier, have been developed to reduce these side-effects
`[2–6]. Although second-generation antihistamines display
`antagonistic actions on H1-receptors, several studies have
`demonstrated that
`the ability of new antihistamines to
`attenuate the production of inflammatory reactions, which
`appear to unrelated to their ability to antagonize the effects
`of histamine at H1-receptor sites [2–6]. Thus, new antihista-
`mines can modulate various inflammatory reactions besides
`their H1-receptor antagonism.
`The pathogenesis of allergic inflammation is complex and
`involves multiple inflammatory cells, cytokines and media-
`tors. The clinical efficacy of oral and topical new antihista-
`mines in allergic diseases and their anti-inflammatory
`actions have been investigated. A number of studies demon-
`strate that new antihistamines reduce clinical symptoms of
`allergic diseases. Several studies support the view that new
`antihistamines have anti-inflammatory effects in vivo [5–15].
`For instance, new antihistamines such as cetirizine and
`azelastine attenuate eosinophil recruitment into the site of
`allergic inflammation [8,14], and intracellular adhesion
`molecule-1 (ICAM-1) expression on epithelial cells from
`the site of allergic inflammation [11,12,14]. Extensive
`studies have been conducted to clarify the mechanism in
`anti-inflammatory actions of new antihistamines;
`these
`actions are outlined as follows:
`X Downregulation:
`Mediator release
`ICAM-1 expression
`Superoxide generation
`Chemotaxis
`Cytokine expression
`X Upregulation:
`Number and function of b2-adrenoceptor
`New antihistamines can attenuate mediator release. For
`
`instance, new antihistamines inhibit histamine release from
`IgE-sensitized basophils [16,17]. In addition, it has also
`been reported that new antihistamines inhibit the synthesis
`and release of arachinoid acid metabolites including leuko-
`triene C4 from mast cells and basophils [16,18]. Interest-
`ingly, new antihistamines inhibit chemical mediator release
`from cells stimulated with not only IgE but also nonimmuno-
`genic agents including calcium ionophore, indicating that
`antihistamines can block IgE receptor-mediated signal
`pathway as well as other intracellular signal transduction
`pathway(s) [2]. New antihistamines attenuate the recruit-
`ment of eosinophils into the sites of allergic inflammation
`via the inhibition of ICAM-1 expression. For instance,
`cetirizine inhibits eosinophil recruitment into the airway
`of allergic bronchial asthmatics challenged with corre-
`sponding allergen [19]. Similarly, cetirizine inhibits
`eosinophil recruitment into the skin induced by platelet-
`activating factor (PAF) [20]. Analysis of the mechanism in
`cetirizine-dependent attenuation of eosinophil recruitment
`into the sites of allergic inflammation has revealed that
`cetirizine selectively inhibits eosinophil adhesion to human
`umbilical vein endothelial cells (HUVEC) but not neutro-
`phils [21]. Subsequent studies have demonstrated that new
`antihistamines such as ketotifen and azelastine inhibit
`ICAM-1
`expression
`on
`tumour
`necrosis
`factor-a
`(TNFa)
`-stimulated HUVEC [22] and nasal epithelial
`cells from the patients with allergic rhinitis challenged
`with corresponding allergen [14,23],
`resulting in the
`attenuation of eosinophil recruitment
`into the sites of
`allergic inflammation. New antihistamines can modulate
`eosinophil functions. Several studies have demonstrated
`that new antihistamines inhibit survival, chemotaxis, gen-
`eration of superoxide and degradation of eosinophils [24–
`28]. Neutrophils are well known to generate superoxide
`anions which cause the tissue damage. Although cetirizine
`dose not inhibit neutrophil recruitment, this drug reduces the
`generation of superoxide anions from neutrophils [29].
`A variety of cells, including lymphocytes, participate in
`the production of allergic inflammation by expressing var-
`ious cytokines. The inhibition of cytokine production which
`promotes allergic inflammation is an important strategy
`controlling allergic inflammation. New antihistamines
`such as azelastine, terfenadine and ketotifen inhibit inter-
`leukin (IL) -2, IL-3, IL-4 and IL-5 production by mitogen-
`stimulated peripheral blood lymphocytes [30], indicating
`that these drugs could attenuate the production of allergic
`inflammation by inhibiting the production of TH2-type
`T-lymphocyte-derived cytokines.
`In addition, cetirizine
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`inhibits monocyte chemotactic protein-1 (MCP-1) and
`RANTES production by interferon-stimulated keratinocytes
`[31]. Interestingly, glucocorticosteroids inhibit the produc-
`tion of IL-8 but not monocyte chemotactic protein-1 (MCP-1)
`and RANTES, indicating that distinct mechanism is involved
`in the regulation of MCP-1 and RANTES production [31].
`Airway epithelial cells are well known to express various
`cytokines which are possibly involved in the production of
`allergic inflammation of the asthmatic airway. In this issue
`of Clinical and Experimental Allergy, Arnold et al. have
`examined the role of cetirizine on IL-8 release from human
`alveolar type U epithelial cell lines, A549 [32]. This study
`demonstrated that cetirizine attenuated IL-8 release by
`TNFa and PMA-stimulated A549, but not by IL-1-b and
`respiratory syncytial virus (RSV)-stimulated A549, indi-
`cating that an inhibition of cetirizine on IL-8 release is
`stimulus-dependent. The promoter of the gene contains
`sequences for binding several nuclear transcription factors.
`Transcriptional factors participate to various extents in the
`inducible expression of the genes. Arnold et al. analysed the
`mechanism in the inhibitory effect of cetirizine on IL-8
`release by airway epithelial cells. The results indicated that
`the attenuation of IL-8 release by cetirizine resulted from
`downregulation of accessible DNA-binding sites of the
`nuclear factor kappa B (NF-kB). H1-receptor antagonist,
`azelastine, has been shown to inhibit IL-1, IL-6, TNFa and
`granulocyte macrophage-colony stimulating factor mRNA
`expression and DNA-binding activity of NF-kB [33]. NF-kB
`participates to various extent in the inducible expression of
`the genes encoding these cytokines. Thus, the inhibition by
`cetirizine and azelastine of cytokine expression might be
`mediated by the inhibition of DNA-binding activity of
`NF-kB. These studies indicate that NF-kB is a molecular
`target of anti-inflammatory actions of new antihistamines.
`However, a precise mechanism remains to be determined.
`b2-adrenergic bronchodilator is widely used to treat
`bronchial asthma. b2-adrenoceptor desensitization may
`occur during long-term treatment of bronchial asthmatics
`the efficacy
`with b2-adrenergic agonists and may limit
`of b2-adrenergic agonists. New antihistamines have favour-
`ite activities which are increasing the density of b2-
`adrenoceptors and preventing downregulation of the number
`of b2-adrenoceptors. The density of b2-adrenoceptor on
`circulating lymphocytes has been regarded as a model
`frequently used to study b2-adrenoceptor function in man.
`Ketotifen increases b2-adrenoceptor density on lympho-
`cytes from bronchial asthmatics who have been treated
`with b2-adrenergic bronchodilator. The increases in density
`and the improvement of functions of b2-adrenoceptors were
`accompanied by a significant increase in peak expiratory
`flow rate in response to inhaled b2-adrenergic bronchodilator,
`salbutamol [34]. In addition, the number of b2-adrenoceptors
`was higher in azelastine and terbutaline-treated guinea pig
`
`lung than that in terbutaline only, showing that azelastine
`may prevent b-adrenergic agonist-induced downregulation
`of the number of b-adrenoceptors [35].
`There are several possible mechanisms by which new
`antihistamines regulate inflammatory reactions: (1) preven-
`tion of an increase in intracellular calcium and interference
`with calcium utilization, (2) modulation of intracellular
`cAMP levels, (3) inhibition of protein kinase C (PKC)
`activity, (4) inhibition of G-protein function, and (5) inhibi-
`tion of NF-kB binding (Fig. 1). An elevation of intracellular
`calcium levels plays an important step in the activation of
`various intracellular signals such as calcium–calmodulin
`cascades and PKC. Catalytic activation of calcium-
`dependent enzymes which can act as intracellular signals
`elicit a variety of cell functions. New antihistamines can
`modulate intracellular calcium-dependent signal transduc-
`tion pathways at several different mechanisms. Ketotifen
`decreases intracellular calcium levels by preventing calcium
`influx [36]. The inhibition of the binding of calcium to
`calcium channels may account for the prevention of calcium
`influx. Azelastine inhibits superoxide generation by neutro-
`phils in response to phorbol myristyl acetate and formyl-
`methionyl-leucyl-phenylalanine and decreases inositol tri-
`phosphate, intracellular free calcium, and PKC activity [37].
`Azelastine can affect calcium–calmodulin pathways. Aze-
`lastine interacts with calmodulin resulting in the inhibition
`of calcium-calmodulin-dependent enzyme, phosphodiester-
`ase [38]. Cetirizine which has ionization and lipophilicity
`behaviour can directly dissolve into the cell membrane and
`stabilize the cell membrane [39], whose pharmacological
`properties may relate to the inhibition of release of calcium
`from intracellular stores. Intracellular cAMP can modulate
`various cell
`functions. Terfenadine,
`inhibits antigen-
`induced histamine release from sensitized guinea pig lung
`and rat peritoneal mast cells [40], and ketotifen also inhibits
`antigen-induced histamine release from human sensitized
`basophils [17], correlating with an increase in intracellular
`cAMP levels which prevents intracellular calcium mobili-
`zation. Azelastine inhibits histamine and TNFa release,
`
`Calcium influx
`Calcium channel
`
`G-protein
`
`Intracellular calcium
`Calcium mobilization
`
`Intracellular cAMP
`
`Protein kinase C
`
`Interacellular calcium store
`Calcium–calmodulin pathway
`
`NF-kB
`
`Cytokine expression
`
`Fig. 1. Intracellular mechanism in anti-inflammatory effects of
`new antihistamines
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`possibly mediating through the inhibition of PKC activity
`[41,42]. Finally, Ko¨ller and colleagues, and Rihoux and
`colleagues have reported that the inhibition by cetirizine
`of mediator release may result from downregulation of
`G-protein activity [43,44]. Consequently, they have pro-
`posed that G-protein might be a molecular target for anti-
`inflammatory actions of cetirizine. They indicate new
`insight into the mechanism in anti-inflammatory actions of
`new antihistamines. There are a variety type of G-proteins
`which individually regulate intracellular signals and cell
`functions; therefore, the identification of G-protein whose
`functions are modulated by cetirizine and the downstream
`signals of G-protein which regulate mediator release remain
`to be determined.
`Quite recently, Tamaoki et al. have shown that azelastine
`inhibits PAF-induced microvascular leakage in airways,
`possibly involving inhibition of the release of neutrophil
`elastase from activated neutrophils [45]. Their results may
`indicate new pharmacological actions of azelastine.
`In summary, histamines play an important role in the
`production of allergic reactions. New antihistamines repre-
`sent the first line of treatment of these conditions, especially
`in nose, conjunctiva and skin. These drugs can modulate
`various inflammatory reactions besides their H1-receptor
`antagonism. The mechanisms in anti-inflammatory actions
`of new antihistamines have been extensively investigated;
`however, further studies focusing on analysis of intracellu-
`lar mechanism in anti-inflammatory effects are needed to
`clarify the anti-inflammatory actions.
`
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`
`S. HAYASHI
`S. HASHIMOTO*
`First Department of Internal Medicine
`Nihon University School of Medicine
`30-1 Oyaguchikamimachi
`Itabashi-ku
`Tokyo 173–8610
`Japan
`
`*Correspondence
`
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