Inhibition of Angiogenic Factor Productions by Quercetin In Vitro and In Vivo.

Takayuki Okumo,Tarou Kimura,Atsuko Furuta,Kanako Yusa,Kazuhito Asano,Masataka Sunagawa

doi:10.3390/medicines8050022

Takayuki Okumo, Tarou Kimura + Show 4 more

Open Access

https://doi.org/10.3390/medicines8050022

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Abstract

Background: Angiogenesis is well known to be an important event in the tissue remodeling observed in allergic diseases. Although there is much evidence that quercetin, one of the most abundant dietary flavonoids, exerts anti-allergic effects in both human and experimental animal models of allergic diseases, the action of quercetin on angiogenesis has not been defined. Therefore, in this study, we first examined the action of quercetin on the secretion of angiogenic factors from murine mast cells in vitro. We also examined the action of quercetin on angiogenic factor secretion in the murine allergic rhinitis model in vivo. Methods: Mast cells (1 × 105 cells/mL) sensitized with ovalbumin (OVA)-specific murine IgE were stimulated with 10.0 ng/mL OVA in the presence or the absence of quercetin for 24 h. The concentrations of angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-α, IL-6 and IL-8 in the supernatants were examined by ELISA. BALB/c male mice immunized with OVA were challenged intranasally with OVA every other day, starting seven days after the final immunization. These mice were then orally administered quercetin once a day for five days, starting seven days after the final immunization. Clinical symptoms were assessed by counting the number of sneezes and nasal rubbing behaviors during the 10 min period just after OVA nasal provocation. The angiogenic factor concentrations in the nasal lavage fluids obtained 6 h after nasal antigenic provocation were examined by ELISA. Results: Quercetin significantly inhibited the production of angiogenetic factors induced by IgE-dependent mechanisms at 5.0 µM or more. Oral administration of 25.0 mg/kg quercetin into the mice also suppressed the appearance of angiogenetic factors in nasal lavage fluids, along with the attenuation of nasal symptoms. Conclusions: These results strongly suggest that the inhibitory action of quercetin on angiogenic factor secretion may be implicated in the therapeutic action of quercetin on allergic diseases, especially allergic rhinitis.

Highlights

Quercetin was first dissolved in dimethyl sulfoxide (DMSO) at a concentration of 100.0 mM and diluted with an RPMI-1640 medium supplemented with 10% Fetal bovine serum (FBS) (RPMI-FBS), so as to give appropriate concentrations for the experiments
The results obtained in this in vitro study clearly showed that quercetin could inhibit angiogenic factor secretion from mast cells induced by antigenic stimulation via the suppression of mRNA expression for angiogenic factors
It is reported that for the oral administration of 1200 mg quercetin, which is the recommended dose as a dietary supplement to healthy humans, blood concentrations of quercetin gradually increased, peaked at 12 μM and decreased to half the peak levels by 24 h after administration [32], which were higher levels showing suppressive effects on angiogenic factor secretion in vitro. These observations, strongly suggest that the present results may reflect the in vivo effect of quercetin on angiogenic factor secretion from mast cells after antigenic stimulation. This may be supported by the observation that oral administration of quercetin at more than 25.0 mg/kg into OVA-sensitized mice was able to decrease the angiogenic factor concentrations in the nasal lavage fluids, which were increased by the intranasal provocation of a specific antigen

Summary

Introduction

Allergic rhinitis (AR) is an IgE-dependent allergic inflammatory disease in the nasal mucosa characterized by nasal itching, sneezing, watery rhinorrhea and nasal obstruction [1,2] These nasal symptoms are accepted to be mainly mediated by several chemical mediators such as histamine, prostaglandins and leukotrienes, which are produced by activated inflammatory cells, especially mast cells, at the site of inflammation [1,2]. Inflammatory cytokines and chemokines like IL-4, IL-13, eotaxin and RANTES are accepted to be implicated in the development and continuation of symptoms of AR [1,2] In addition to these responses, structural alterations in the nasal wall have been observed in AR patients. We examined the action of quercetin on angiogenic factor secretion in the murine allergic rhinitis model in vivo. Conclusions: These results strongly suggest that the inhibitory action of quercetin on angiogenic factor secretion may be implicated in the therapeutic action of quercetin on allergic diseases, especially allergic rhinitis

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