Lee CG, 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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    • "Udowodniono, iż histamina zwiększa wytwarzanie VEGF prawdopodobnie za pośrednictwem receptora histaminowego typu 2 [31]. VEGF jest wytwarzany przez komórki nabłonka dróg oddechowych oraz przez limfocyty pomocnicze typu 2 (T helper -Th2), na których również stwierdzono obecność receptorów VEGF [57] [61]. Ponadto eozynofile aktywowane przez IL-5 i czynnik stymulujący tworzenie kolonii granulocytów i makrofagów GM-CSF stanowią istotne źródło tej cytokiny [39]. "
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    ABSTRACT: The vascular endothelial growth factor (VEGF) is produced by different types of cells and has a major role in both, physiological and pathological angiogenesis. On the one hand VEGF is a strong mitotic and chemotactic factor for the endothelial cells, stimulating thus formation of new vessels, while on the other, it enhances the vascular endothelium permeability of the existing blood vessels which contributes to development and persistence of the inflammatory conditions. In the latter its activity is by 50 000 times higher than that of histamine. VEGF facilitates formation of oedema and leukocyte migration from the circulation to the site of inflammation. VEGF is also important in remodeling of the extracellular matrix. Moreover, it has an important significance in regulation of the immunological response, therefore plays a role in autoaggressive phenomena as well as immediate- and delayed-type hypersensitivity. Its role in the pathogenesis of immunological and inflammatory diseases, including allergy, asthma and different skin disorders has been indicated.
    Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 01/2014; 68:57-65. DOI:10.5604/17322693.1086360 · 0.57 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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