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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 6

WFA protects from pulmonary fibrosis in bleomycin mice model.

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WFA protects from pulmonary fibrosis in bleomycin mice model.
(A) Schema...
(A) Schematic of animal model and WFA treatment (B) LC3B II puncta formation, as assessed by immunofluorescence staining for LC3B (green) and nuclei (DAPI, blue) in paraffin embedded mouse lung sections on day 21. Scale bar: 100 μm. Bleo., bleomycin. (C) Quantification of intensity of LC3BII puncta in immunofluorescently labeled mouse lung sections by ImageJ. (D) Immunoblot analysis and (E) densitometry for beclin 1, p62, vimentin, and LC3B in whole lung homogenates from C57BL/6 mice subjected to control saline, bleomycin, WFA, and bleomycin and WFA treatment on day 21. β-Actin served as loading control. Data are representative of 3 experiments. (F) Representative images and measurement of invasiveness (zone of invasion percent) in pulmospheres prepared from lung cells from C57BL/6 mice subjected to control saline, bleomycin, WFA and bleomycin/WFA on day 21. Scale bars: 100 μm. (G) Representative images of immunofluorescence staining for vimentin (green), LC3B (red), and nucleus (DAPI, blue) in pulmospheres prepared from mouse lungs cells after 21 days of bleomycin and bleomycin/WFA exposure. Scale bar: 50 μm (H) MicroCT analysis of mouse lungs on day 20. (I) Fibrosis, as assessed on day 21 by H&E staining. Collagen deposition was analyzed using Picrosirius staining and IHC analysis of Col 1. Scale bar: 100 μm. (J) Lung homogenates analyzed on day 21 for hydroxyproline content. Values represent means ±SD, n = 5. *P < 0.05, **P < 0.01, ***P < 0.001.

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