Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis
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
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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Research Article Inflammation Pulmonology

Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis

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 4

Transgenic VEGFA overexpression reduced bleomycin-induced lung fibrosis.

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Transgenic VEGFA overexpression reduced bleomycin-induced lung fibrosis....
VEGFA overexpression was induced by doxycycline 3 days before bleomycin administration and was maintained by doxycycline in the drinking water. (A–D) Bleomycin-induced collagen gene expression at day 14 as measured by quantitative PCR (qPCR) (A), whole lung collagen protein levels at day 14 measured by Sircol assay (B), representative lung sections stained with Masson’s trichrome to depict the degree of fibrosis at day 14 in WT and VEGF-Tg mice that received bleomycin or vehicle (PBS) (C), and fibrosis semiquantified using modified Ashcroft score analysis (D). (E) In a separate study, VEGF overexpression was induced for 7 days prior to bleomycin administration and whole lung collagen protein analyzed using the Sircol assay 14 days after bleomycin. (F–H) Fold change in whole lung gene expression 14 days after bleomycin as measured by qPCR in Acta1 (F); Tgfb1, Ctgf, and Mmp12 (G); and Wisp1 and Cd44 (H) gene expression in WT and VEGF-Tg mice that had 3 days of VEGF overexpression prior to bleomycin administration. In the event a gene was undetectable, it was set as zero for this comparison. Bars represent mean ± SEM. n = 3–5 WT mice per group, n = 7–12 VEGF-Tg mice. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.005, ****P ≤ 0.001 induced by bleomycin in comparison with the relevant strain control, or ##P ≤ 0.01, ###P ≤ 0.005, ####P ≤ 0.001 comparing VEGF-Tg with WT bleomycin challenged mice via two-way ANOVA analysis.