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Lee GG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V et al.Vascular endothelial growth factor (VEGF) induces remodeling and enhances Th2-mediated sensitization and inflammation in the lung. Nat Med 10:1095-1103

University of California, San Francisco, San Francisco, California, United States
Nature Medicine (Impact Factor: 28.05). 11/2004; 10(10):1095-103. DOI: 10.1038/nm1105
Source: PubMed

ABSTRACT Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF(165) transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (T(H)2)-mediated inflammation. In these mice, VEGF induced, through IL-13-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and T(H)2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by T(H)2 versus T(H)1 cells. In this setting, it had a critical role in T(H)2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive T(H)2 inflammation. VEGF regulation may be therapeutic in asthma and other T(H)2 disorders.

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    • "Our study also shows that AT reduced the expression of TGF-β and VEGF. These AR inducers have been previously demonstrated to stimulate fibroblasts to produce extracellular matrix proteins (Cho et al., 2005; Harris et al., 2013) and to induce parenchyma and vascular remodeling, edema and airway hyperresponsiveness (Lee et al., 2004; Meyer & Akdis, 2013). Furthermore, TGF-β and VEGF have been associated with reductions in lung function (Asai et al., 2003; Kelly et al., 2010; Wang et al., 2011). "
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    ABSTRACT: The purpose of this study was to determine the effect of aerobic exercise training (AT) on the expression of glucocorticoid receptors (GR) and anti-inflammatory cytokines in an asthma model. BALB/c mice were divided into groups control (CT; nonsensitized/nontrained), aerobic training (AT; nonsensitized/trained), ovalbumin (OVA; sensitized/not trained), and OVA+AT (sensitized/trained). OVA groups received OVA by inhalation, and the AT groups completed 1, 3, or 7 days of exercise (60 min/session). Expression of GR, IL-4, IL-5, IL-10, IL-1ra, NF-κB, TGF-β, VEGF, ICAM-1, VCAM-1; eosinophils counting; and airway remodeling (AR) features [airway smooth muscle (ASM) and epithelial thickness and collagen fiber deposition] were quantified. OVA sensitization induced a decrease in the expression of GR and increases in the eosinophil, IL-4, IL-5, NF-κB, TGF-β, VEGF, ICAM-1, VCAM-1, and AR features (P < 0.05). After 3 days, AT reversed the OVA-induced reduction in the expression of GR, and subsequently induced increases in the expression of IL-10 and IL-1ra (seventh day). In contrast, the eosinophil migration, the expression of NF-κB, IL-4, IL-5, TGF-β, RANTES, VEGF, ICAM-1, VCAM-1, and the AR features (P < 0.05) were reduced. AT increases the expression of GR and anti-inflammatory cytokines (IL-10 and IL-1ra) and reduces the expression of inflammatory mediators and airway inflammation in an animal model of asthma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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    • "All of the transgenic animals have been crossed with WTs for more than six generations. The generation and phenotype of the CC10­rtTA­VEGF and CC10­rtTA–IL­13 transgenic mice in which ex­ pression of human VEGF 165 and mouse IL­13, respectively, is under the con­ trol of an inducible promoter has been described previously (Zhu et al., 1999; Lee et al., 2004). Mice were grown to 6–8 wk, and expression of the trans­ gene was induced by adding 1 g/liter doxycycline to their drinking water for 7–10 d. "
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    ABSTRACT: Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.
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    • "In conclusion, our previous observations (Nkyimbeng-Takwi, Chapoval 2011; Smith et al. 2011) and our new data reported here suggest that a regulatory effect of Sema4D in allergic asthma is a complex venue which can not be simplified by its role in DC – T cell interaction and involves other cells, lung resident cells and inflammatory cells, many of which express functional receptors for Sema4D (Kumanogoh et al. 2000; Ishida et al. 2003; Kumanogoh, Kikutani 2003; Nkyimbeng-Takwi, Chapoval 2011; Smith et al. 2011). Besides its role in immune cell activation and function (Kumanogoh, Kikutani 2003), Plexin B1 plays an important role in cell migration (Delaire et al. 2001; Basile, Afkhami, Gutkind 2005) and angiogenesis (Basile et al. 2004; Conrotto et al. 2005; Basile et al. 2007) which both are critical components of asthma pathogenesis (Lee et al. 2004; Velazquez, Teran 2011; Islam, Luster 2012; Meyer, Akdis 2012). Thus, despite the recent significant advances in the biology, distribution and function of Sema4D, the understanding of a complex venue of its regulation of different immunological diseases is still in the early stage in terms of understanding the exact role of each Sema4D-expressing cellular component in modulating allergic response. "
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