Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis
Shin-Ichi Nureki, … , Surafel Mulugeta, Michael F. Beers
Shin-Ichi Nureki, … , Surafel Mulugeta, Michael F. Beers
Published June 19, 2018
Citation Information: J Clin Invest. 2018;128(9):4008-4024. https://doi.org/10.1172/JCI99287.
View: Text | PDF
Research Article Pulmonology Article has an altmetric score of 71

Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis

  • Text
  • PDF
Abstract

Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell–restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc (SP-CI73T). Tamoxifen-treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7–14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA content of select inflammatory cytokines. Resolution of alveolitis (2–4 weeks), commensurate with a rise in TGF-β1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, α–smooth muscle actin–positive (α-SMA–positive) cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis.

Authors

Shin-Ichi Nureki, Yaniv Tomer, Alessandro Venosa, Jeremy Katzen, Scott J. Russo, Sarita Jamil, Matthew Barrett, Vivian Nguyen, Meghan Kopp, Surafel Mulugeta, Michael F. Beers

×

Figure 10

IER-SP-CI73TFlp mice express IPF biomarkers.

Options: View larger image (or click on image) Download as PowerPoint
IER-SP-CI73TFlp mice express IPF biomarkers.
Western blotting of BALF (2...
Western blotting of BALF (20 μl/lane) for OPN (A), SP-D (B), and MMP-7 (C) from IER-SP-CI73T/I73TFlp+/– mice obtained at 3 days to 6 weeks after tamoxifen as indicated. Controls (Ctl) consisted of IER-SP-CI73T/I73TFlp–/– mice 2 weeks after tamoxifen treatment. Densitomteric band intensities, expressed as relative units (A), percent control (B), or fold increase (C), are presented as dot plots with mean ± SEM. *P < 0.05 versus IER-SP-CI73T/I73TFlp–/– (CTL) by 1-way ANOVA followed by Tukey’s post hoc test. (D) ELISA for IL-6 content of BALF obtained 1, 2, and 6 weeks after tamoxifen treatment. Dot plots with mean ± SEM are shown for IER-SP-CI73T/I73TFlp+/– mice (black dots) and IER-SP-CI73T/I73TFlp–/– controls (gray dots). At all 3 time points, controls were below the limit of detection. *P < 0.05 versus IER-SP-CI73T/I73TFlp–/– by 1-way ANOVA followed by Tukey’s post hoc test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 9 news outlets
Blogged by 1
Posted by 18 X users
On 1 Facebook pages
141 readers on Mendeley
See more details