title: Formoterol and budesonide inhibit rhinovirus infection and cytokine production in primary cultures of human tracheal epithelial cells.
abstract: BACKGROUND
  Long-acting β(2) agonists (LABAs) and inhaled corticosteroids (ICSs) reduce the frequency of exacerbations of chronic obstructive pulmonary disease and bronchial asthma. However, inhibitory effects of LABAs and ICSs on the replication of rhinovirus (RV), the major cause of exacerbations, have not been demonstrated.
  
  
  METHODS
  Primary cultures of human tracheal epithelial cells were infected with a major group RV, type 14 rhinovirus (RV14), to examine the effects of formoterol and budesonide on RV infection and infection-induced airway inflammation.
  
  
  RESULTS
  Treatment with formoterol and budesonide 72 h before and after RV14 infection reduced RV14 titers and cytokine concentrations, including interleukin (IL)-1β, IL-6 and IL-8, in supernatants and viral RNA within cells. Formoterol and budesonide reduced mRNA expression and protein concentration of intercellular adhesion molecule-1 (ICAM-1), the receptor for RV14. Formoterol reduced the number and fluorescence intensity of acidic endosomes through which RV RNA enters the cytoplasm. Formoterol and budesonide reduced the activation of the nuclear factor kappa-B protein p65 in nuclear extracts. The effects of formoterol plus budesonide were additive with respect to RV14 replication, cytokine production, ICAM-1 expression, acidic endosome fluorescence intensity, and p65 activation. The selective β(2)-adrenergic receptor antagonist, ICI 118551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol], reversed the inhibitory effects of formoterol on RV14 titers and RNA levels, the susceptibility of cells to RV14 infection, cytokine production, acidic endosomes, ICAM-1 expression, and p65 activation.
  
  
  CONCLUSIONS
  Formoterol and budesonide may inhibit RV infection by reducing the ICAM-1 levels and/or acidic endosomes and modulate airway inflammation associated with RV infections.
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: myamaya@med.tohoku.ac.jp.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Yamaya
authors.affiliation: Virus Research Center, Clinical Research Division, Sendai National Hospital, Sendai, Japan. Electronic address: hide-nishimura@mte.biglobe.ne.jp.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: nadinececile@med.tohoku.ac.jp.
authors.forename: Lusamba
authors.initials: L
authors.lastname: Nadine
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: hkubo@med.tohoku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: nagatomi@med.tohoku.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nagatomi
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000368:Aged; D019819:Budesonide / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology*; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D010850:Picornaviridae Infections / Q000821:virology*; D012367:RNA, Viral / Q000378:metabolism; D012229:Rhinovirus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D014132:Trachea / Q000166:cytology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D016207:Cytokines; D004983:Ethanolamines; D005938:Glucocorticoids; D012367:RNA, Viral; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D019819:Budesonide; D000068759:Formoterol Fumarate
keywords: Inhaled corticosteroid; Intercellular adhesion molecule; Long-acting β(2) agonist; Rhinovirus; Tracheal epithelial cell