Montelukast prevents microparticle-induced inflammatory and functional alterations in human bronchial smooth muscle cells

• Published in: Pharmacological research 2013-10, Vol.76, p.149-156
• Main Authors: Fogli, Stefano, Stefanelli, Fabio, Neri, Tommaso, Bardelli, Claudio, Amoruso, Angela, Brunelleschi, Sandra, Celi, Alessandro, Breschi, Maria Cristina
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Active Transport, Cell Nucleus - drug effects; Airway smooth muscle cell; Anti-Asthmatic Agents - pharmacology; Bronchi - cytology; Bronchial inflammation; Cell Line; Cell signaling; Cell-Derived Microparticles - immunology; Cells, Cultured; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - immunology; Gene Expression Regulation - drug effects; Humans; Interleukin-8 - genetics; Interleukin-8 - immunology; Microparticles; Monocytes - cytology; Monocytes - immunology; Montelukast; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - immunology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; NF-kappa B - analysis; NF-kappa B - immunology; NF-kappa B - metabolism; Quinolines - pharmacology; Receptors, Adrenergic, beta - immunology; Signal Transduction - drug effects; β2-Agonists
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2013.08.001

Microparticles (MPs) are membrane fragments that may play a role in the pathogenesis of chronic respiratory diseases. We aimed to investigate whether human monocytes/macrophage-derived MPs could induce a pro-inflammatory phenotype in human bronchial smooth muscle cells (BSMC) and the effect of montelukast in this setting. Experimental methods included isolation of human monocytes/macrophages and generation of monocyte-derived MPs, RT-PCR analysis of gene expression, immunoenzymatic determination of pro-inflammatory factor release, bioluminescent assay of intracellular cAMP levels and electromobility shift assay analysis of NF-κB nuclear translocation. Stimulation of human BSMC with monocyte-derived MPs induced a pro-inflammatory switch in human BSMC by inducing gene expression (COX-2 and IL-8), protein release in the supernatant (PGE2 and IL-8), and heterologous β2-adrenoceptor desensitization. The latter effect was most likely related to autocrine PGE2 since pre-treatment with COX inhibitors restored the ability of salbutamol to induce cAMP synthesis in desensitized cells. Challenge with MPs induced nuclear translocation of NF-κB and selective NF-κB inhibition decreased MP-induced cytokine release in the supernatant. Montelukast treatment prevented IL-8 release and heterologous β2-adrenoceptor desensitization in human BSMC exposed to monocyte-derived MPs by blocking NF-κB nuclear translocation. These findings provide evidence on the role of human monocyte-derived MPs in the airway smooth muscle phenotype switch as a novel potential mechanism in the progression of chronic respiratory diseases and on the protective effects by montelukast in this setting.