The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy

Abstract

Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous clinical trials of H1 receptor antagonists (H1RAs) as a treatment for asthma were not successful. In recent years, type 2 innate immunity has been demonstrated to be involved in allergic airway inflammation. Allergic asthma is defined by IgE antibody-mediated mast cell degranulation, while group 2 innate lymphoid cells (ILC2) induce eosinophilic inflammation in nonallergic asthma without allergen-specific IgE. Anti-IgE therapy has demonstrated prominent efficacy in the treatment of severe allergic asthmatics sensitized with specific perennial allergens. Furthermore, recent trials of specific cytokine antagonists indicated that these antagonists were effective in only some subtypes of asthma. Accordingly, H1RAs may show significant clinical efficacy for some subtypes of allergic asthma in which histamine is deeply associated with the pathophysiology.

Keywords: IgE; OCT-3; Th2 cell; airway obstruction; allergen; allergic rhinitis; histamine receptor; histamine receptor 1 antagonist; histamine transporter; innate immunity; type 2 innate lymphoid cells.

Figure 1

Percentage of mast cells in BAL fluids in asthmatics (BA: ●), patients with other pulmonary diseases (PD): interstitial pneumonia (□), sarcoidosis (△), and chronic obstructive pulmonary diseases (■), and control patients (CP: ○). (Bars indicate SEM). The figure was modified from reference [11] with permission: Tomioka et al., Mast cells in bronchoalveolar lumen of patients with bronchial asthma. Am. Rev. Respir. Dis. 1984, 129, 1000–1005.

Figure 2

The effects of terfenadine on bronchoconstriction induced by (A) Histamine and (B) Allergen. Terfenadine (dotted curve) significantly attenuated bronchoconstriction induced by allergic challenge. (Solid curves indicate pretreatment with terfenadine. Dotted curves indicate pretreatment with placebo. The figure was modified from reference [16] with permission: Rafferty et al., The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5’ monophosphate in atopic asthma. Am. Rev. Respir. Dis. 1987, 13, 369–373.

Figure 3

Effect of SKF 91488 and aminoguanidine on contractile response of human bronchi to histamine. Dose–response curves to histamine in SKF 91488 (10⁻⁴ M) and control are analyzed. Data are expressed as percentage of response to acetylcholine (10⁻³ M). Histamine N-methyltransferase (HMT) regulates contraction of airway smooth muscle by histamine. HMT in epithelium degrades histamine actively. The figure was modified from reference [19] with permission: Yamauchi et al., Structure and function of human histamine N-methyltransferase: critical enzyme in histamine metabolism in airway. Am. J. Physiol. 1994, 267, L342–L349.

Figure 4

Scheme of histamine transport system through OCT-3. (A) Inward transport of histamine in bronchial epithelial cells. Genetic polymorphisms of OCT-3 affect the inward transport activity of histamine, resulting in the increased amounts of histamine in extracellular space and possibly confer stronger stimulation on H1R and induce contraction of bronchial smooth muscle cells. (B) Outward transport system of histamine through OCT-3 in professional histamine-producing cells (mast cells and basophils). Genetic polymorphisms of OCT-3 affect the outward transport activity of histamine, resulting in the decreased amounts of histamine contents in the vesicles through homeostatic mechanisms.

Figure 5

Time course of allergen-induced early and late airway reaction after different treatment strategies in the subjects. Pulmonary function, expressed as percent of postdiluent FEV 1, was followed hourly for 12 h. The figure was modified from reference [45] with permission: Roquet et al., Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am. J. Respir. Crit. Care Med. 1997, 155, 1856–1863.

Figure 6

Regulation of Th1 and Th2 responses by histamine via H1R and H2R.

Figure 7

The therapeutic use of H1RAs to the comorbidity of asthma and allergic rhinitis. More than 60% of asthmatics represented the comorbidity with allergic rhinitis.