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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 1

Vimentin expression is upregulated at the margins of IPF fibrotic foci.

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Vimentin expression is upregulated at the margins of IPF fibrotic foci.
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(A) IHC staining showing IgG control and expression of vimentin in formalin-fixed, paraffin-embedded tissue section of a representative subject with IPF. Scale bars: 100 μm. Area outlined in red is the invasive front of fibrotic foci (outlined in blue). (B) Quantification of DAB-positive vimentin-expressing cells in the center and at the cellular cuffs of fibrotic foci. Graph shows representative results for an individual subject (n = 5). Each dot represents DAB intensity per area. Data are represented as mean ± SD. (C) Representative image of the expression of vimentin in pulmospheres obtained from the cells isolated from control and IPF lung tissue. The pulmospheres were seeded for an hour in collagen gel prior to immunostaining for vimentin (red). Nuclei were stained with DAPI (blue). Scale bars: 100 μm. (D) Quantification of vimentin-positive cells in pulmospheres from controls and IPF subjects. Data are represented as mean ± SD. Each dot represents an individual subject. *P < 0.05, ***P < 0.001.

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