title: TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment.
abstract: The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.
authors: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA.
authors: Amber L
authors: AL
authors: Degryse
authors: Harikrishna
authors: H
authors: Tanjore
authors: Xiaochuan C
authors: XC
authors: Xu
authors: Vasiliy V
authors: VV
authors: Polosukhin
authors: Brittany R
authors: BR
authors: Jones
authors: Chad S
authors: CS
authors: Boomershine
authors: Camila
authors: C
authors: Ortiz
authors: Taylor P
authors: TP
authors: Sherrill
authors: Frank B
authors: FB
authors: McMahon
authors: Linda A
authors: LA
authors: Gleaves
authors: Timothy S
authors: TS
authors: Blackwell
authors: William E
authors: WE
authors: Lawson
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D001761:Bleomycin / Q000009:adverse effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D055370:Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D001616:beta-Galactosidase