title: Montelukast prevents microparticle-induced inflammatory and functional alterations in human bronchial smooth muscle cells.
abstract: 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.
authors: Department of Pharmacy, University of Pisa, Pisa, Italy. Electronic address: stefano.fogli@farm.unipi.it.
authors: Stefano
authors: S
authors: Fogli
authors: Fabio
authors: F
authors: Stefanelli
authors: Tommaso
authors: T
authors: Neri
authors: Claudio
authors: C
authors: Bardelli
authors: Angela
authors: A
authors: Amoruso
authors: Sandra
authors: S
authors: Brunelleschi
authors: Alessandro
authors: A
authors: Celi
authors: Maria Cristina
authors: MC
authors: Breschi
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology*; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000276:immunology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D003521:Cyclopropanes; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides
chemical_list: D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D016209:Interleukin-8; D016328:NF-kappa B; D011804:Quinolines; D011943:Receptors, Adrenergic, beta; D013440:Sulfides; D051546:Cyclooxygenase 2; C093875:montelukast
keywords: Airway smooth muscle cell; Bronchial inflammation; Cell signaling; Indomethacin (PubChem CID 3715); Microparticles; Montelukast; Montelukast sodium (PubChem CID 23663996); NS398 (PubChem CID 4553); Salbutamol emisulphate (PubChem CID 39859); β2-Agonists