title: Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma.
abstract: Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear.
  
  
  
  We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness.
  
  
  
  Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of TH2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization.
  
  
  
  Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among TH2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization.
  
  
  
  These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, TH2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness.
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; San Francisco VA Medical Center and Northern California Institute for Research and Education, San Francisco, Calif.
authors.forename: Kelly
authors.initials: K
authors.lastname: Sweerus
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, Calif.
authors.forename: Marrah
authors.initials: M
authors.lastname: Lachowicz-Scroggins
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif.
authors.forename: Erin
authors.initials: E
authors.lastname: Gordon
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; San Francisco VA Medical Center and Northern California Institute for Research and Education, San Francisco, Calif.
authors.forename: Michael
authors.initials: M
authors.lastname: LaFemina
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, Calif.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; San Francisco VA Medical Center and Northern California Institute for Research and Education, San Francisco, Calif.
authors.forename: Mihir
authors.initials: M
authors.lastname: Parikh
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif.
authors.forename: Cindy
authors.initials: C
authors.lastname: Kanegai
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, Calif.
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of California, San Francisco, Calif; San Francisco VA Medical Center and Northern California Institute for Research and Education, San Francisco, Calif. Electronic address: James.frank@ucsf.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Frank
mesh_terms: D000328:Adult; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001190:Arylsulfonates / Q000378:metabolism; D001230:Aspergillus / Q000276:immunology; D001249:Asthma / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D057167:Claudins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D018793:Interleukin-13 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D000946:Antigens, Fungal; D001190:Arylsulfonates; C486683:CLDN18 protein, human; D057167:Claudins; C438899:Cldn18 protein, mouse; D018793:Interleukin-13; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007073:Immunoglobulin E; C005047:pyranine
keywords: Asthma; airway hyperresponsiveness; antigen sensitization; epithelial barrier function; epithelium; tight junction