title: Regional differences in susceptibiity of bronchial epithelium to mesenchymal transition and inhibition by the macrolide antibiotic azithromycin.
abstract: OBJECTIVE
  Dysregulated repair following epithelial injury is a key forerunner of disease in many organs, and the acquisition of a mesenchymal phenotype by the injured epithelial cells (epithelial to mesenchymal transition, EMT) may serve as a source of fibrosis. The macrolide antibiotic azithromycin and the DNA synthesis inhibitor mycophenolate are in clinical use but their mechanism of action remains unknown in post-transplant bronchiolitis obliterans syndrome (BOS). Here we determined if regional variation in the EMT response to TGFβ1 underlies the bronchiolocentric fibrosis leading to BOS and whether EMT could be inhibited by azithromycin or mycophenolate.
  
  
  RESULTS
  We found that small and large airway epithelial cells from stable lung transplant patients underwent EMT when stimulated with TGFβ1, however mesenchymal protein expression was higher and loss of epithelial protein expression more complete in small airway epithelial cells. This regional difference was not mediated by changes in expression of the TGFβRII or Smad3 activation. Azithromycin potentially inhibited EMT in both small and large airway epithelial cells by inhibiting Smad3 expression, but not activation.
  
  
  CONCLUSIONS
  Collectively, these observations provide a biologic basis for a previously unexplained but widely observed clinical phenomena, and a platform for the development of new approaches to fibrotic diseases.
authors.affiliation: School of Paediatrics and Child Health, the University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Balarka
authors.initials: B
authors.lastname: Banerjee
authors.forename: Michael
authors.initials: M
authors.lastname: Musk
authors.forename: Erika N
authors.initials: EN
authors.lastname: Sutanto
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Yerkovich
authors.forename: Peter
authors.initials: P
authors.lastname: Hopkins
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.forename: Suzanna
authors.initials: S
authors.lastname: Lindsey-Temple
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Stick
authors.forename: Anthony
authors.initials: A
authors.lastname: Kicic
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chambers
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D017963:Azithromycin