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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.
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Research Article Pulmonology

Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury

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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

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Figure 2

Vimentin expression is upregulated during attenuated autophagy in IPF fibroblasts.

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Vimentin expression is upregulated during attenuated autophagy in IPF fi...
(A) Immunoblot analysis of vimentin and the autophagic markers beclin 1 and LC3BII in cell lysates of fibroblasts from age-matched subjects (n = 5) and IPF (n = 5) lung tissue in complete medium (control) and serum-starved conditions. β-Actin served as loading control. Densitometry analysis of protein expression in Western blot for (B) vimentin, (C) beclin 1, and (D) LC3BII/LC3BI normalized with β-actin in controls and IPF fibroblasts. *P < 0.05. (E) Invasiveness in the pulmospheres obtained from age-matched subjects and IPF lung in complete medium and serum-starved conditions. Data are presented as mean ± SD; each dot represents an individual patient. **P < 0.01. Vimentin expression in complete medium and serum-starved conditions in pulmospheres from age-matched subjects and IPF patients (F) (scale bars: 200 μm); quantitation by FACS analysis of vimentin-positive cells in dissociated pulmospheres (G). (H) Single invasive fibroblast in pulmospheres (scale bars: 10 μm).

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