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Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis
Lynne A. Murray, … , Cory M. Hogaboam, Erica L. Herzog
Lynne A. Murray, … , Cory M. Hogaboam, Erica L. Herzog
Published August 17, 2017
Citation Information: JCI Insight. 2017;2(16):e92192. https://doi.org/10.1172/jci.insight.92192.
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Research Article Inflammation Pulmonology

Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis

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Abstract

The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell–derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium.

Authors

Lynne A. Murray, David M. Habiel, Miriam Hohmann, Ana Camelo, Huilan Shang, Yang Zhou, Ana Lucia Coelho, Xueyan Peng, Mridu Gulati, Bruno Crestani, Matthew A. Sleeman, Tomas Mustelin, Meagan W. Moore, Changwan Ryu, Awo D. Osafo-Addo, Jack A. Elias, Chun G. Lee, Buqu Hu, Jose D. Herazo-Maya, Darryl A. Knight, Cory M. Hogaboam, Erica L. Herzog

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Figure 1

Reduced VEGF in the lungs of IPF patients.

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Reduced VEGF in the lungs of IPF patients.
(A) Reduced levels of lung-ti...
(A) Reduced levels of lung-tissue VEGFA were measured by microarray and compared with Mann-Whitney U analysis. (B) Luminex-based comparison of VEGF in idiopathic pulmonary fibrosis (IPF) lung tissue (n = 13) compared with normal lung tissue taken from the normal nonfibrotic margins of lung tumor resection (n = 11). Data were normalized to total mg protein and compared with Mann-Whitney U evaluation. (C) Decreased bronchoalveolar lavage (BAL) VEGF was measured in IPF (n = 28) compared with non-IPF (n = 17) BAL, as measured by luminex and compared by Mann-Whitney U test. (D) Spontaneous release of VEGF from primary normal lung (NL) fibroblasts and IPF lung tissue–derived fibroblasts after 72 hours of culture and compared with ANOVA. In A–C, bars represent median and interquartile range, and in D, bars represent mean ± SEM. *P < 0.05, ***P ≤ 0.005, ****P ≤ 0.001 or as stated.

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

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