Hypergravity enhances the therapeutic effect of dexamethasone in allergic asthma and rhinitis animal model

Abstract

We investigated whether the therapeutic effects of dexamethasone for allergic asthma and rhinitis were enhanced in mice when exposed to hypergravity. Forty mice were divided into 5 groups (n = 8/group): Control group received saline intraperitoneally (i.p.) and intranasally (i.n.); Asthma group received i.p./i.n. ovalbumin (OVA) for inducing allergic asthma/rhinitis; Dexa group received i.n. dexamethasone (0.75 mg/kg) 30 minutes before each OVA challenge; Hypergravity group was subjected to allergic asthma/rhinitis as well as exposed to 5 G hypergravity for 30 days; Finally in Dexa/Hypergravity group, hypergravity and dexamethasone were used simultaneously during induction of allergic asthma/rhinitis. Dexa group and Hypergravity group showed a significant decrease in serum total IgE levels compared to the Asthma group (p<0.05). Dexa/Hypergravity group showed greater IgE decrease compared with Dexa group (p = 0.040). Compared with the monotherapy groups, Dexa/Hypergravity group showed significantly fewer eosinophils in BAL fluid (p<0.05). Dexa/Hypergravity group showed significantly decreased eosinophilic infiltration into the lungs and nasal cavity (p<0.05). EC-SOD (extracellular superoxide dismutase) expression was significantly upregulated in the Hypergravity group and Dexa/Hypergravity group, compared with the Dexa group (p<0.05). In conclusion, hypergravity enhanced the therapeutic effect of dexamethasone in a murine model of allergic asthma and rhinitis. Therefore, combination could be a promising strategy, and one of its mechanisms could be up-regulation of EC-SOD expression.

Fig 1. Study protocol for the induction of allergic asthma and rhinitis and/or exposure to hypergravity.

Fig 2. Serum levels of total IgE and ovalbumin (OVA)-specific IgE.

* Significant difference from the control group, p < 0.05; ** significant difference from the control group, p < 0.01; $ significant difference from the asthma group, p < 0.05 (the Kruskal-Wallis and Mann-Whitney U tests).

Fig 3. Number of eosinophils, neutrophils, and lymphocytes in the broncho-alveolar lavage fluid.

* Significant difference from the control group, p < 0.05; ** significant difference from the control group, p < 0.01; *** significant difference from the control group, p < 0.001; $ significant difference from the asthma group, p < 0.05; $ $ significant difference from the asthma group, p < 0.01; $ $ $ significant difference from the asthma group, p < 0.001 (the Kruskal-Wallis and Mann-Whitney U tests).

Fig 4. Levels of IL-4, IL-5, and IL-13 in the broncho-alveolar lavage fluid (upper column) and expression of IL-4, IL-5, and IL-13 gene in the lung homogenate, analyzed using PCR (lower column).

* Significant difference from the control group, p < 0.05; ** significant difference from the control group, p < 0.01; *** significant difference from the control group, p < 0.001; $ significant difference from the asthma group, p < 0.05; $ $ significant difference from the asthma group, p < 0.01; $ $ $ significant difference from the asthma group, p < 0.001 (the Kruskal-Wallis and Mann-Whitney U tests).

Fig 5. Histological observations of the lung and nasal cavity (upper column, Figs 5a_1 and 5a_2), and the number of infiltrated eosinophils into 1 mm² of lung parenchyma and lamina papyracea of the nasal cavity (lower column, Fig 5b).

* Significant difference from the control group, p < 0.05; ** significant difference from the control group, p < 0.01; $ significant difference from the asthma group, p < 0.05; $ $ significant difference from the asthma group, p < 0.01; $ $ $ significant difference from the asthma group p < 0.001 (the Kruskal-Wallis and Mann-Whitney U tests).

Fig 6. Expression of extracellular superoxide dismutase (EC-SOD), Hypoxia-inducible factor-1α (Hif-1α), Vascular endothelial growth factor (VEGF), Cyclo-oxygenase-2 (COX-2), caspase-3, and heme oxygenase-1 (HO-1) genes, evaluated by real-time PCR.

* Significant difference from the control group, p < 0.05; ** significant difference from the control group, p < 0.01; *** significant difference from the control group, p < 0.001; $ significant difference from the asthma group, p < 0.05; $ $ significant difference from the asthma group, p < 0.01; $ $ $ significant difference from the asthma group, p < 0.001 (the Kruskal-Wallis and Mann-Whitney U tests).