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: 27.36). 11/2004; 10(10):1095-103. DOI: 10.1038/nm1105
Source: PubMed


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.
    Scandinavian Journal of Medicine and Science in Sports 02/2015; DOI:10.1111/sms.12411 · 2.90 Impact Factor
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    • "VEGF also stimulates leukocyte migration to endothelial cells by promoting ICAM-1 and VCAM-1 expression, suggesting the proinflammatory role of VEGF in allergic response [41]. Furthermore, overexpression of VEGF induces enhanced allergic sensitization, upregulation of Th2-type inflammatory responses, and mucous gland hyperplasia [42]. Thus, inhibition of VEGF activity has been proposed as a potential therapeutic strategy in allergic airway disease. "
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    ABSTRACT: Vascular endothelial growth factor (VEGF) is supposed to contribute to the pathogenesis of allergic airway disease. VEGF expression is regulated by a variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible factor-1 alpha (HIF-1α). Recently, inhibition of the mammalian target of rapamycin (mTOR) has been shown to alleviate cardinal asthmatic features, including airway hyperresponsiveness, eosinophilic inflammation, and increased vascular permeability in asthma models. Based on these observations, we have investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. Next, the mechanisms by which mTOR is activated to modulate this response have been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase (PI3K)/Akt or protein kinase C-delta (PKC δ) in various cell types. Consistent with these, our results have revealed that suppression of PKC δ by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC δ is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may represent a valuable target for innovative therapeutic treatment of allergic airway disease.
    PLoS ONE 11/2013; 8(11):e81773. DOI:10.1371/journal.pone.0081773 · 3.23 Impact Factor
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    • "Interestingly, Dang et al have recently demonstrated that HIF-1α plays an important role in the alternate induction of TH17 cells [56]. Furthermore inhibition of HIF-1α attenuated OVA-induced AHR and inflammation via VEGF suppression in bronchial epithelium [57], which is a critical effector molecule in Th2 driven allergic disease in the lung [58,59]. "
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    ABSTRACT: Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro. To determine the anti-inflammatory potential of anthraquinones in-vivo. BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation. Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung. Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.
    PLoS ONE 11/2013; 8(11):e79565. DOI:10.1371/journal.pone.0079565 · 3.23 Impact Factor
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