Role of histamine in the pathophysiology of asthma: immunomodulatory and anti-inflammatory activities of H1-receptor antagonists

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Abstract

Cumulative clinical and laboratory evidence on histamine and its actions suggests that it has a pathophysiologic role in asthma. These findings have renewed interest in the potential therapeutic role of H1 antihistamines in this disease. A murine model of allergen-induced airway inflammation and methacholine-induced airway hyperresponsiveness has been used to clarify mechanisms of airway function, to identify potential therapeutic targets, and to investigate the effects of the H1-receptor antagonist fexofenadine. Findings suggest that there may be a role for second-generation antihistamines in treating asthma, with patient selection as well as dosing both important therapeutic considerations. Because high-dose therapy may be required to achieve a clinical response, agents with the widest therapeutic window and the lowest potential for sedation would offer the greatest therapeutic potential.

Section snippets

Actions of histamine

During allergic reactions, both immunologic and nonimmunologic triggers stimulate release of histamine from cytoplasmic granules of mast cells and basophils. Depending on the location of these cells, histamine release causes such symptoms as acute rhinitis, bronchospasm, diarrhea, cramping, or cutaneous wheal and flare responses.1, 2 The majority of the acute symptoms in urticaria, allergic rhinitis, and allergic asthma are the result of the very rapid activity of histamine on vascular

Histamine mediators

Histamine triggers its effects by activating one of the histamine-type membrane receptors. The H1 receptor possesses all of the structural features of G-protein–coupled receptors, including 7 transmembrane domains, amino terminal glycosylation sites, and protein kinase A and protein kinase C phosphorylation sites.9 H1 receptors have been detected in the mammalian brain,10 airway smooth muscle,11, 12 gastrointestinal tract,13 genitourinary system,14 vascular smooth muscle,15 endothelial cells,5

Histamine implicated in pathophysiology of asthma

A number of findings point to a pathophysiologic role for histamine in asthma. Histamine has been detected in the airways of asthmatic persons, even during asymptomatic periods,22, 23, 24 and an increased number of degranulated mast cells and basophils have been detected in biopsies of asthmatic airways, even when the biopsies were obtained long after an acute asthma attack.25, 26 The level of histamine in bronchoalveolar lavage fluid (BALF) has been found to correlate with the severity of

Clinical trials of antihistamines in asthma

Because many of the effects of histamine on macrophages, dendritic cells, endothelial cells, and epithelial cells can be prevented by H1-receptor antagonists (Table 2),28, 29, 30, 31 there has been a resurgence of interest in the potential of these agents in the treatment of asthma. The potential efficacy of H1 antihistamines in asthma has been under investigation for >50 years.32 Inhalation of chlorpheniramine and clemastine was found to produce acute bronchodilation,33, 34 but these compounds

Identifying therapeutic targets

We have used a murine model of allergen-induced airway inflammation and methacholine-induced airway hyperresponsiveness to clarify mechanisms of airway function, to identify potential therapeutic targets, and to investigate the effects of the H1-receptor antagonist fexofenadine.64, 65, 66, 67, 68, 69, 70 In this model, the BALB/c strain of mice were sensitized to ovalbumin and then rechallenged with allergen 2 weeks later. Airway responsiveness to inhaled methacholine was assessed 2 days after

Conclusions

It would appear that if there is a role for second- or third-generation antihistamines in the treatment of asthma, patient selection and dosing are important considerations. Histamine may be a dominant pathophysiologic factor in patients with mild to moderately severe seasonal asthma, and the inflammation and symptoms that ensue may be susceptible to H1-receptor antagonist blockade. However, clinical trials as well as in vitro and laboratory investigations suggest that H1 antagonists may have

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