title: Claudin-1 expression in airway smooth muscle exacerbates airway remodeling in asthmatic subjects.
abstract: BACKGROUND
  Increased airway smooth muscle (ASM) mass is an essential component of airway remodeling and asthma development, and there is no medication specifically against it. Tight junction (TJ) proteins, which are expressed in endothelial and epithelial cells and affect tissue integrity, might exist in other types of cells and display additional functions in the asthmatic lung.
  
  
  OBJECTIVE
  The aim of this study was to investigate the existence, regulation, and function of TJ proteins in ASM in asthmatic patients.
  
  
  METHODS
  The expression and function of TJ proteins in primary ASM cell lines, human bronchial biopsy specimens, and a murine model of asthma were analyzed by means of RT-PCR, multispectral imaging flow cytometry, immunohistochemistry, Western blotting, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester staining, tritiated thymidine incorporation, wound-healing assay, and luminometric bead array.
  
  
  RESULTS
  Increased claudin-1 expression was observed in ASM of asthmatic patients, as well as in a murine model of asthma-like airway inflammation. Whereas IL-1β and TNF-α upregulated claudin-1 expression, it was downregulated by the T(H)2 cytokines IL-4 and IL-13 in primary human ASM cells. Claudin-1 was localized to the nucleus and cytoplasm but not to the cell surface in ASM cells. Claudin-1 played a central role in ASM cell proliferation, as demonstrated by increased ASM cell proliferation seen with overexpression and decreased proliferation seen with small interfering RNA knockdown of claudin-1. Overexpression of claudin-1 induced vascular endothelial growth factor and downregulated IL-6, IL-8, and IFN-γ-induced protein 10 production by ASM cells. Claudin-1 upregulation by IL-1β or TNF-α was suppressed by dexamethasone but not by rapamycin, FK506, or salbutamol.
  
  
  CONCLUSIONS
  These results demonstrate that claudin-1 might play a role in airway remodeling in asthmatic patients by means of regulation of ASM cell proliferation, angiogenesis, and inflammation.
authors.affiliation: Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujita
authors.forename: Maciej
authors.initials: M
authors.lastname: Chalubinski
authors.forename: Claudio
authors.initials: C
authors.lastname: Rhyner
authors.forename: Philippe
authors.initials: P
authors.lastname: Indermitte
authors.forename: Norbert
authors.initials: N
authors.lastname: Meyer
authors.forename: Ruth
authors.initials: R
authors.lastname: Ferstl
authors.forename: Angela
authors.initials: A
authors.lastname: Treis
authors.forename: Enrique
authors.initials: E
authors.lastname: Gomez
authors.forename: Ahmet
authors.initials: A
authors.lastname: Akkaya
authors.forename: Liam
authors.initials: L
authors.lastname: O'Mahony
authors.forename: Mübeccel
authors.initials: M
authors.lastname: Akdis
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D062445:Claudin-1; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018793:Interleukin-13 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012137:Respiratory System / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C568108:CLDN1 protein, human; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D016207:Cytokines; D017931:DNA Primers; C508598:IL4 protein, human; D018793:Interleukin-13; D053583:Interleukin-1beta; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D003907:Dexamethasone