title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
abstract: Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1fl/flmice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF.SPC-Cre TRF1fl/flmice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Ram P
authors.initials: RP
authors.lastname: Naikawadi
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Supparerk
authors.initials: S
authors.lastname: Disayabutr
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Benat
authors.initials: B
authors.lastname: Mallavia
authors.affiliation: Department of Anatomy, School of Medicine, University of California, San Francisco, California, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Donne
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Green
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: La
authors.affiliation: Department of Anatomy, School of Medicine, University of California, San Francisco, California, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Rock
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
mesh_terms: D056809:Alveolar Epithelial Cells / Q000166:cytology*; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells; D054990:Idiopathic Pulmonary Fibrosis; D008168:Lung / Q000473:pathology*; D051379:Mice; D011658:Pulmonary Fibrosis / Q000473:pathology*; D016615:Telomere / Q000473:pathology*; D059506:Telomere Shortening