title: Region-specific role for Pten in maintenance of epithelial phenotype and integrity.
abstract: Previous studies have demonstrated resistance to naphthalene-induced injury in proximal airways of mice with lung epithelial-specific deletion of the tumor-suppressor gene Pten, attributed to increased proliferation of airway progenitors. We tested effects of Pten loss following bleomycin injury, a model typically used to study distal lung epithelial injury, in conditional PtenSFTPC-creknockout mice. Pten-deficient airway epithelium exhibited marked hyperplasia, particularly in small bronchioles and at bronchoalveolar duct junctions, with reduced E-cadherin and β-catenin expression between cells toward the luminal aspect of the hyperplastic epithelium. Bronchiolar epithelial and alveolar epithelial type II (AT2) cells in PtenSFTPC-cremice showed decreased expression of epithelial markers and increased expression of mesenchymal markers, suggesting at least partial epithelial-mesenchymal transition at baseline. Surprisingly, and in contrast to previous studies, mutant mice were exquisitely sensitive to bleomycin, manifesting rapid weight loss, respiratory distress, increased early mortality (by day 5), and reduced dynamic lung compliance. This was accompanied by sloughing of the hyperplastic airway epithelium with occlusion of small bronchioles by cellular debris, without evidence of increased parenchymal lung injury. Increased airway epithelial cell apoptosis due to loss of antioxidant defenses, reflected by decreased expression of superoxide dismutase 3, in combination with deficient intercellular adhesion, likely predisposed to airway sloughing in knockout mice. These findings demonstrate an important role for Pten in maintenance of airway epithelial phenotype integrity and indicate that responses to Pten deletion in respiratory epithelium following acute lung injury are highly context-dependent and region-specific.
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Per
authors.initials: P
authors.lastname: Flodby
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Janice M
authors.identifier: 0000-0002-4166-6197
authors.initials: JM
authors.lastname: Liebler
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Sunohara
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Castillo
authors.affiliation: Departments of Medicine and Biomedical Sciences, Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: McConnell
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Manda S
authors.initials: MS
authors.lastname: Krishnaveni
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Agnes
authors.initials: A
authors.lastname: Banfalvi
authors.affiliation: Division of Neonatalogy, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Departments of Medicine and Biomedical Sciences, Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Barry
authors.initials: B
authors.lastname: Stripp
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.|Mork Family Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California; and.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.affiliation: Division of Neonatalogy, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; zborok@med.usc.edu.|Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California.|Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D015820:Cadherins / Q000378:metabolism; D003187:Compliance; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006965:Hyperplasia; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D007365:Intercellular Junctions / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008648:Mesoderm / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism*; D013194:Staining and Labeling; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015820:Cadherins; D012333:RNA, Messenger; D001761:Bleomycin; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase
keywords: adherens junctions; alveolar epithelium; bleomycin; cell adhesion; reactive oxygen species