Differential Effects of Salbutamol and Montelukast on Eosinophil Adhesion and Superoxide Anion Generation

Abstract

Background: β₂-Agonists, a representative class of bronchodilators used for asthma, have been shown to modulate some functions of eosinophils, including cell adhesion. Similarly, a leukotriene receptor antagonist (LTRA) may be beneficial in controlling inflammation in asthma, as cysteinyl leukotrienes (cysLTs) can cause accumulation or activation of eosinophils. Recent evidence suggests that the addition of an LTRA, but not a long-acting β₂-agonist, to inhaled corticosteroid additionally reduces the number of eosinophils in sputum and blood from patients with asthma. The present study examined whether a β₂-agonist and an LTRA differentially modify eosinophil adhesion and activation induced by cysLTs and other activators. Methods: Eosinophils were isolated from blood of healthy donors and then incubated in the presence or absence of salbutamol (albuterol) or montelukast. Eosinophils were then exposed to leukotriene D₄ (LTD₄) or another activator, and the generation of superoxide anion (O₂^–) was evaluated by cytochrome C reduction assay. Eosinophil adhesion was examined by an eosinophil peroxidase assay. Results: Montelukast, but not salbutamol (both at 1 µM), inhibited LTD₄-induced (100 nM) eosinophil adhesion to recombinant human intercellular adhesion molecule 1. Both drugs similarly and partially inhibited the 100 pM interleukin-5-induced adhesive response of eosinophils to recombinant human intercellular adhesion molecule 1. Montelukast, but not salbutamol, blocked LTD₄-induced eosinophil O₂^– generation of eosinophils. Finally, neither salbutamol nor montelukast modified phorbol myristate acetate (1 ng/ml)-induced O₂^– generation from eosinophils. Conclusion: These results confirm that LTD₄ directly induces activation of eosinophils via the cysLT1 receptor. Furthermore, the results suggest that a β₂-agonist has no effect on eosinophil adhesion and activation induced by cysLTs. These results explain the differential effects of an LTRA and a β₂-agonist in the treatment of eosinophilic inflammation in asthma.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…In a recent study, the CysLT 1 R has been associated with cytokine transduction signals for the up-regulation of eosinophilopoiesis by IL-13 and eotaxin in murine bone marrow (Queto et al, 2010). These data support early reports demonstrating the inhibitory action of CysLT 1 R antagonists on eosinophil activation and migration (Virchow et al, 2001;Fregonese et al, 2002;Suzuki et al, 2003;Ueda et al, 2003;Saito et al, 2004;Nagata et al, 2005), as well as on adhesion (Fregonese et al, 2002;Nagata et al, 2002;Kushiya et al, 2006;Meliton et al, 2007;Profita et al, 2008). There is considerable information available to demonstrate the ability of CysLTR antagonists to reduce airway eosinophilia and eosinophil cationic protein (ECP) in animals (Underwood et al, 1996;Ihaku et al, 1999) and in humans (Pizzichini et al, 1999;Obase et al, 2002;Steinke et al, 2003;Strauch et al, 2003;Laitinen et al, 2005;Kopriva et al, 2006).…”

Nasal Eosinophilia and Serum Soluble Intercellular Adhesion Molecule 1 in Patients with Allergic Rhinitis Treated with Montelukast Alone or in Combination with Desloratadine or Levocetirizine

“…It is well known that AR is associated with increased secretion levels of proinflammatory cytokines and overexpression of adhesion molecules (endothelial-leukocyte adhesion molecule-1, lymphocyte function-associated antigen-1, and ICAM-1) in allergic mucosa, which regulate cell infiltration. Because histamine 30 and cysteinyl leukotrienes 31,32 as well as IL-1, 33 IL-8, 34 and TNF- α 35 cause enhanced ICAM-1 surface expression and eosinophil adhesion, it is plausible that antihistamine and antileukotriene therapy may cooperate in inhibition of eosinophilic inflammation.…”

“…37 In both human and animal models, montelukast as well as second-generation antihistamines attenuated migration of eosinophils into the airways during an immune challenge. 27,32,40 Thus, it is possible that antihistamines and montelukast may contribute to the inhibition of allergic inflammation by the down-regulation of ICAM-1 in endothelial and epithelial cells and by decreasing serum levels of sICAM-1. It is noteworthy that such an additive effect still has not been assessed.…”

Effect of Montelukast Monotherapy on Oxidative Stress Parameters and DNA Damage in Children with Asthma

“…Eosinophil superoxide anion generation is induced by LT D 4 [14]. All these effects of cysteinyl LTs can be blocked by LT receptor antagonists in vivo [11,15,16]. In recent years, a growing body of evidence suggests that activity of NADPH oxidase (NOX) is stimulated by LT B 4 via the LT B 4 receptor 2 (BLT2).…”