title: House dust mites induce proliferation of severe asthmatic smooth muscle cells via an epithelium-dependent pathway.
abstract: BACKGROUND
  Asthma is a frequent airway disease, and asthma control determinants have been associated with indoor allergen sensitization. The most frequent allergens are house dust mites (HDM), which act in vivo on the bronchial epithelial layer. Severe asthma has also been associated with bronchial remodeling and more specifically with increased mass of bronchial smooth muscle (BSM). However, the relationship between HDM stimulation of the bronchial epithelial layer and BSM remodeling is unknown.
  
  
  OBJECTIVE
  To evaluate whether epithelial stimulation with HDM induces BSM cell proliferation in subjects with severe asthma.
  
  
  METHODS
  A total of 22 subjects with severe asthma and 27 subjects with no asthma were recruited. We have developed an in vitro culture model combining an epithelium layer in air-liquid interface (ALI) interacting with BSM. We assessed BSM proliferation using BrdU incorporation. We explored the role of epithelium-derived mediators using reverse-transcriptase polymerase chain reaction (RT-PCR) and ELISA in vitro and in vivo. Finally, leukotrienes receptor expression was assessed in vitro by flow cytometry and RT-PCR and ex vivo by laser microdissection and RT-PCR.
  
  
  RESULTS
  We found that epithelial stimulation by HDM selectively increased the proliferation of asthmatic BSM cells and not that of nonasthmatic cells. The mechanism involved epithelial protease-activated receptor-2-dependent production of leukotrienes C4 associated with an overexpression of leukotrienes receptor CysLTR1 by asthmatic BSM cells in vitro and ex vivo.
  
  
  CONCLUSIONS
  This work demonstrates the selective role of HDM on BSM remodeling in patients with severe asthma and points out different therapeutic targets at epithelial and smooth muscle levels.
authors.affiliation: 1 Département de Pharmacologie and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trian
authors.forename: Benoit
authors.initials: B
authors.lastname: Allard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dupin
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Carvalho
authors.forename: Olga
authors.initials: O
authors.lastname: Ousova
authors.forename: Elise
authors.initials: E
authors.lastname: Maurat
authors.forename: Jehan
authors.initials: J
authors.lastname: Bataille
authors.forename: Matthieu
authors.initials: M
authors.lastname: Thumerel
authors.forename: Hugues
authors.initials: H
authors.lastname: Begueret
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Girodet
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.forename: Patrick
authors.initials: P
authors.lastname: Berger
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000503:physiopathology*; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000502:physiology; D004848:Epithelium / Q000502:physiology; D005260:Female; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D039981:Pyroglyphidae / Q000276:immunology*; D018077:Receptors, Leukotriene / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D018077:Receptors, Leukotriene; C083173:leukotriene C4 receptor; D017997:Leukotriene C4
keywords: asthma; bronchi; epithelium; remodeling; smooth muscle