Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils

Abstract

The research question addressed in the current study was: do formoterol (1 and 10 nM) and montelukast (2 mM) possess interactive inhibitory effects on activated human neutrophils, particularly in relation to alterations in cyclic AMP and cytosolic Ca 2+ fluxes?Isolated human blood neutrophils were activated with the chemoattractant N-formyl-Lmethionyl-L-leucyl-L-phenylalanine (fMLP) (1 mM) in combination with cytochalasin B (CB; 3 mM). Fura-2-acetoxymethyl ester-based spectrofluorimetry, lucigenin-enhanced chemiluminescence, colorimetric and flow cytometric procedures were used to measure cytosolic Ca 2+ fluxes, production of superoxide, elastase release and beta-2 integrin (CR3) expression, respectively, while cyclic AMP and leukotriene (LT)B 4 were assayed using competitive binding ELISA procedures. Activation of the cells with fMLP/CB resulted in abrupt and sustained increases in cytosolic Ca 2+, as well as release of elastase and production of superoxide and LTB 4 , and expression of CR3, all of which were attenuated by formoterol and montelukast individually, and especially by the combination of these agents. These anti-inflammatory effects of each agent, as well as the combination, were associated with significant increases in cyclic AMP.The findings of the current study may explain the efficacy of montelukast and formoterol when used in combination with inhaled corticosteroids in the treatment of severe asthma, possibly by controlling neutrophil-driven inflammation of the airways.

Effect of beta2-adrenergic agonists on eosinophil adhesion, superoxide anion generation, and degranulation

“…63 Gravett et al speculated that the local concentration of formoterol is approximately 10 nM (assuming a maximal single dose of 24 mg, lung deposition of 18.6%, and a tidal volume of 500 ml). 26 Although the actual concentration in the airway is more difficult to ascertain, the concentration of more than 1 mM in the inflammation cites seems to be hard to achieve after formoterol treatment during asthma attack.…”

Effect of Formoterol on Eosinophil Trans-Basement Membrane Migration Induced by Interleukin-8-Stimulated Neutrophils

“…Therefore, formoterol may affect these chemoattractants and reduce the TBM of eosinophils. A recent study indicates that formoterol attenuates production of superoxide and LTB 4 on activated neutrophils by fMLP via association with increases of cyclic adenosine monophosphate [21]. MMP-9 may be a target as another potential mechanism.…”

“…Formoterol itself has various kinds of anti-inflammatory effects. Formoterol is known to suppress the production of superoxide-anion and the release of elastase by formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophils in vitro [21]. Formoterol also attenuates neutrophil numbers and IL-8 levels in the sputum of asthmatic patients [15].…”

Current Administration of Antileukotrienes in Adults With Asthma

“…Показа-но, что его применение приводит к неспецифичес-кому ингибированию циклических нуклеотидных фосфодиэстераз, особенно фосфодиэстеразы-4, ре-зультатом которого является цАМФ-зависимое по-давление провоспалительной активности нейтрофи-лов [32]. Комбинация формотерола и монтелукаста оказывает аддитивный противовоспалительный эф-фект, повышая внутриклеточную концентрацию цАМФ через активацию β2-адренорецепторов и ин-гибирование фосфодиэстераз [33], что может объяс-нять эффективность комбинированной терапия иГКС с β2-агонистами длительного действия и анта-гонистами рецепторов LT при лечении тяжелой БА.…”