title: Defective epithelial barrier function in asthma.
abstract: BACKGROUND
  Asthma is a complex disease involving gene and environment interactions. Although atopy is a strong predisposing risk factor for asthma, local tissue susceptibilities are required for disease expression. The bronchial epithelium forms the interface with the external environment and is pivotally involved in controlling tissue homeostasis through provision of a physical barrier controlled by tight junction (TJ) complexes.
  
  
  OBJECTIVE
  To explain the link between environment exposures and airway vulnerability, we hypothesized that epithelial TJs are abnormal in asthma, leading to increased susceptibility to environmental agents.
  
  
  METHODS
  Localization of TJs in bronchial biopsies and differentiated epithelial cultures was assessed by electron microscopy or immunostaining. Baseline permeability and the effect of cigarette smoke and growth factor were assessed by measurement of transepithelial electrical resistance and passage of fluorescently labeled dextrans.
  
  
  RESULTS
  By using immunostaining, we found that bronchial biopsies from asthmatic subjects displayed patchy disruption of TJs. In differentiated bronchial epithelial cultures, TJ formation and transepithelial electrical resistance were significantly lower (P < .05) in cultures from asthmatic donors (n = 43) than from normal controls (n = 40) and inversely correlated with macromolecular permeability. Cultures from asthmatic donors were also more sensitive to disruption by cigarette smoke extract. Epidermal growth factor enhanced basal TJ formation in cultures from asthmatic subjects (P < .01) and protected against cigarette smoke-induced barrier disruption (P < .01).
  
  
  CONCLUSIONS
  Our results show that the bronchial epithelial barrier in asthma is compromised. This defect may facilitate the passage of allergens and other agents into the airway tissue, leading to immune activation and may thus contribute to the end organ expression of asthma.
authors.affiliation: Synairgen Research Ltd, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Chang
authors.initials: C
authors.lastname: Xiao
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Puddicombe
authors.forename: Sarah
authors.initials: S
authors.lastname: Field
authors.forename: Joel
authors.initials: J
authors.lastname: Haywood
authors.forename: Victoria
authors.initials: V
authors.lastname: Broughton-Head
authors.forename: Ilaria
authors.initials: I
authors.lastname: Puxeddu
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vernon-Wilson
authors.forename: David
authors.initials: D
authors.lastname: Sammut
authors.forename: Nicole
authors.initials: N
authors.lastname: Bedke
authors.forename: Catherine
authors.initials: C
authors.lastname: Cremin
authors.forename: Jody
authors.initials: J
authors.lastname: Sones
authors.forename: Ratko
authors.initials: R
authors.lastname: Djukanović
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.forename: Jane E
authors.initials: JE
authors.lastname: Collins
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Phillip
authors.initials: P
authors.lastname: Monk
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
mesh_terms: D000818:Animals; D001249:Asthma / Q000473:pathology; D001706:Biopsy; D001980:Bronchi / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003911:Dextrans / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D012907:Smoking; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology*; D014026:Nicotiana
chemical_list: D003911:Dextrans; D004815:Epidermal Growth Factor