Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury
Ranu Surolia, … , Victor J. Thannickal, Veena B. Antony
Ranu Surolia, … , Victor J. Thannickal, Veena B. Antony
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e123253. https://doi.org/10.1172/jci.insight.123253.
View: Text | PDF
Research Article Pulmonology

Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury

  • Text
  • PDF
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival of 3–5 years following diagnosis. Lung remodeling by invasive fibroblasts is a hallmark of IPF. In this study, we demonstrate that inhibition of vimentin intermediate filaments (VimIFs) decreases the invasiveness of IPF fibroblasts and confers protection against fibrosis in a murine model of experimental lung injury. Increased expression and organization of VimIFs contribute to the invasive property of IPF fibroblasts in connection with deficient cellular autophagy. Blocking VimIF assembly by pharmacologic and genetic means also increases autophagic clearance of collagen type I. Furthermore, inhibition of expression of collagen type I by siRNA decreased invasiveness of fibroblasts. In a bleomycin injury model, enhancing autophagy in fibroblasts by an inhibitor of VimIF assembly, withaferin A (WFA), protected from fibrotic lung injury. Additionally, in 3D lung organoids, or pulmospheres, from patients with IPF, WFA reduced the invasiveness of lung fibroblasts in the majority of subjects tested. These studies provide insights into the functional role of vimentin, which regulates autophagy and restricts the invasiveness of lung fibroblasts.

Authors

Ranu Surolia, Fu Jun Li, Zheng Wang, Huashi Li, Kevin Dsouza, Vinoy Thomas, Sergey Mirov, Dolores Pérez-Sala, Mohammad Athar, Victor J. Thannickal, Veena B. Antony

×

Figure 4

WFA-regulated autophagy is beclin 1 dependent.

Options: View larger image (or click on image) Download as PowerPoint
WFA-regulated autophagy is beclin 1 dependent.
(A) Immunoblot analysis a...
(A) Immunoblot analysis and densitometry for beclin 1 and LC3B of cell lysates from nontargeted siRNA– and beclin 1 siRNA–transfected (siNT- and siBeclin1-transfected) IPF fibroblasts treated with WFA. β-Actin served as loading control. Data are representative of 3 experiments. (B) Immunoblot analysis and densitometry of collagen I (Col1), vimentin, and beclin 1 from cell lysates from siNT- and siBeclin1-transfected IPF fibroblasts treated with WFA. β-Actin served as loading control. Data are representative of 3 experiments. *P < 0.05, **P < 0.01, ***P < 0.001. (C) Representative image and measurement of invasiveness (percent zone of invasion) in beclin 1 siRNA–transfected IPF pulmospheres. siNT was used as control. Scale bars: 100 μm. **P < 0.01, compared with siNT fibroblasts. (D) Immunoprecipitation studies with anti–beclin 1 antibodies of cell lysates from IPF fibroblasts treated with vehicle and WFA. The graph represents vimentin/beclin 1 binding ratio. Precipitates were immunoblotted for associated beclin 1 and vimentin, and whole cell lysates (WCL) for LC3B, vimentin, and beclin 1 antibodies. β-Actin served as loading control for cell lysates. (E) Immunostaining for beclin 1 (green) and vimentin (red) in IPF fibroblasts treated in the absence or presence of WFA. Scale bars: 20 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts