title: β-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin.
abstract: BACKGROUND
  Alveolar epithelial cells (AECs) play central roles in the response to lung injury and the pathogenesis of pulmonary fibrosis.
  
  
  OBJECTIVE
  We aimed to determine the role of β-catenin in alveolar epithelium during bleomycin-induced lung fibrosis.
  
  
  METHODS
  Genetically modified mice were developed to selectively delete β-catenin in AECs and were crossed to cell fate reporter mice that express β-galactosidase (βgal) in cells of AEC lineage. Mice were given intratracheal bleomycin (0.04 units) and assessed for AEC death, inflammation, lung injury, and fibrotic remodeling. Mouse lung epithelial cells (MLE12) with small interfering RNA knockdown of β-catenin underwent evaluation for wound closure, proliferation, and bleomycin-induced cytotoxicity.
  
  
  RESULTS
  Increased β-catenin expression was noted in lung parenchyma after bleomycin. Mice with selective deletion of β-catenin in AECs had greater AEC death at 1 week after bleomycin, followed by increased numbers of fibroblasts and enhanced lung fibrosis as determined by semiquantitative histological scoring and total collagen content. However, no differences in lung inflammation or protein levels in bronchoalveolar lavage were noted. In vitro, β-catenin-deficient AECs showed increased bleomycin-induced cytotoxicity as well as reduced proliferation and impaired wound closure. Consistent with these findings, mice with AEC β-catenin deficiency showed delayed recovery after bleomycin.
  
  
  CONCLUSIONS
  β-Catenin in the alveolar epithelium protects against bleomycin-induced fibrosis. Our studies suggest that AEC survival and wound healing are enhanced through β-catenin-dependent mechanisms. Activation of the developmentally important β-catenin pathway in AECs appears to contribute to epithelial repair after epithelial injury.
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN 37232-2650, USA.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.forename: Amber L
authors.initials: AL
authors.lastname: Degryse
authors.forename: Peter F
authors.initials: PF
authors.lastname: Crossno
authors.forename: Xiaochuan C
authors.initials: XC
authors.lastname: Xu
authors.forename: Melinda E
authors.initials: ME
authors.lastname: McConaha
authors.forename: Brittany R
authors.initials: BR
authors.lastname: Jones
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bryant
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.forename: Frank B
authors.initials: FB
authors.lastname: McMahon
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D004195:Disease Models, Animal; D004848:Epithelium; D020287:In Situ Nick-End Labeling; D055370:Lung Injury / Q000139:chemically induced / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology*; D014945:Wound Healing / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051176:beta Catenin; D001761:Bleomycin