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ISU201 enhances the resolution of airway inflammation in a mouse model of an acute exacerbation of asthma.

ABSTRACT: Glucocorticoids are commonly used for treating asthma and its exacerbations but have well-recognised adverse effects and are not always effective. Few alternative treatments exist. Using a murine model of an acute exacerbation of asthma, we assessed the ability of ISU201, a novel protein drug, to suppress the inflammatory response when administered after induction of an exacerbation. Sensitised mice were chronically challenged with a low mass concentration of aerosolised ovalbumin, and then received a single moderate-level challenge to simulate an allergen-induced exacerbation. ISU201 was administered to mice 2 and 8 hours later, while pulmonary inflammation and expression of mRNA for chemokines and proinflammatory cytokines were assessed after 4, 12, and 24 hours. Relative to vehicle-treated controls, ISU201 suppressed accumulation of pulmonary neutrophils and eosinophils, while accelerating the decline in CXCL1, TNF-?, and IL-6 in lavage fluid and lung tissue. ISU201 significantly reduced peak expression of mRNA for the chemokines Cxcl9 and Cxcl10, the adhesion molecules Icam1 and Vcam1, and the proinflammatory cytokines Il1b, Il12p40, and Csf1. The ability of ISU201 to promote resolution of inflammation suggests that it may have potential as an alternative to glucocorticoids in the management of asthma, including when administered after the onset of an acute exacerbation.

SUBMITTER: Hiroshima Y

PROVIDER: S-EPMC4342076 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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ISU201 enhances the resolution of airway inflammation in a mouse model of an acute exacerbation of asthma.

Hiroshima Yuka Y Garthwaite Linda L Hsu Kenneth K Yoo Hyouna H Park Sang-Ho SH Geczy Carolyn L CL Kumar Rakesh K RK Herbert Cristan C

Mediators of inflammation 20150212

Glucocorticoids are commonly used for treating asthma and its exacerbations but have well-recognised adverse effects and are not always effective. Few alternative treatments exist. Using a murine model of an acute exacerbation of asthma, we assessed the ability of ISU201, a novel protein drug, to suppress the inflammatory response when administered after induction of an exacerbation. Sensitised mice were chronically challenged with a low mass concentration of aerosolised ovalbumin, and then rece ...[more]

PMID: 25767333

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Project description:BACKGROUND:Loki zupa (Luooukezupa) decoction, consisting of the roots of Hyssopuscuspidatus Boriss (Shenxiangcao) and Irishalophila Pall root (Yuanweigen), is commonly used in Uygur medicine to treat asthma. However, the mode of action of this material has yet to be elucidated. This study aims to investigate the effects of Loki zupa decoction on the airway inflammation of an ovalbumin (OVA)-induced asthma mouse model. METHODS:Mice were divided into normal control (NC), asthma (A), high, medium and low doses of Loki zupa decoction (L 14.0, L 7.0, L 3.5), water extract (LW), n-butanol extract (LN), ethyl acetate extract (LE) and dexamethasone (DEX) groups. Antiasthmatic model was induced by OVA sensitization and challenged using BALB/c mice. Airway hyperresponsiveness (AHR) toward methacholine (Mch) was assessed using Buxco equipment. Lung inflammation was measured by hematoxylin and eosin staining and bronchoalveolar lavage fluid (BALF) cell count and classification. Inflammatory cytokines in BALF and serum were analyzed by Bio-Plex assay, and mRNA levels were investigated by qPCR analysis. The roots of H. Boriss (250 g) and I. Pall (250 g) were decocted, concentrated and diluted to 14.0, 7.0 and 3.5 g crude herb/kg body weight. The LW, LN and LE of the Loki zupa decoction were prepared and diluted to a dose equivalent to 7 g of crude herb/kg body weight. RESULTS:Loki zupa decoction and its extracts significantly attenuated the AHR towards Mch (all P < 0.05). Treatment with Loki zupa decoction and its extracts relieved the infiltration of inflammatory cells in and around the airways, and reduced the total white blood cell (all P < 0.05), neutrophil (all P < 0.05), monocyte (all P < 0.05) and eosinophil (all P < 0.05) counts in the BALF. The BALF samples collected from the mice treated with the Loki zupa decoction and its extracts had lower levels of IL-1? (all P < 0.05), TNF-? (all P < 0.05), IL-2 (all P < 0.05), IL-4 (P = 0.047) and IL-5 (all P < 0.05). The serum samples of these mice also had lower IL-1? (all P < 0.05), TNF-? (all P < 0.05), IL-4 (all P < 0.05) and IL-5 (all P < 0.05) levels and higher levels of IFN-? (P < 0.001) compared with the OVA-induced asthma mouse model. qPCR analysis revealed that Loki zupa decoction and its extracts inhibited mRNA expression of IL-4 (all P < 0.05), IL-5 (all P < 0.05) and IL-13 (all P < 0.05) and promoted mRNA expression of IFN-? (all P < 0.05) in asthmatic mice. CONCLUSION:Loki zupa decoction reduced AHR, attenuated airway inflammation, promoted Th1 and suppressed Th2 cell functions in an OVA-induced asthma mouse model.

Project description:Nanotechnology has the capacity to revolutionize numerous fields and processes, however, exposure-induced health effects are of concern. The majority of nanoparticle (NP) safety evaluations have been performed utilizing healthy models and have demonstrated the potential for pulmonary toxicity. A growing proportion of individuals suffer diseases that may enhance their susceptibility to exposures. Specifically, metabolic syndrome (MetS) is increasingly prevalent and is a risk factor for the development of chronic diseases including type-2 diabetes, cardiovascular disease, and cancer. MetS is a combination of conditions which includes dyslipidemia, obesity, hypertension, and insulin resistance. Due to the role of lipids in inflammatory signaling, we hypothesize that MetS-associated dyslipidemia may modulate NP-induced immune responses. To examine this hypothesis, mice were fed either a control diet or a high-fat western diet (HFWD) for 14-weeks. A subset of mice were treated with atorvastatin for the final 7-weeks to modulate lipids. Mice were exposed to silver NPs (AgNPs) via oropharyngeal aspiration and acute toxicity endpoints were evaluated 24-h post-exposure. Mice on the HFWD demonstrated MetS-associated alterations such as increased body weight and cholesterol compared to control-diet mice. Cytometry analysis of bronchoalveolar lavage fluid (BALF) demonstrated exacerbation of AgNP-induced neutrophilic influx in MetS mice compared to healthy. Additionally, enhanced proinflammatory mRNA expression and protein levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and interleukin-6 were observed in MetS mice compared to healthy following exposure. AgNP exposure reduced mRNA expression of enzymes involved in lipid metabolism, such as arachidonate 5-lipoxygenase and arachidonate 15-lipoxygenase in both mouse models. Exposure to AgNPs decreased inducible nitric oxide synthase gene expression in MetS mice. An exploratory lipidomic profiling approach was utilized to screen lipid mediators involved in pulmonary inflammation. This assessment indicates the potential for reduced levels of lipids mediators of inflammatory resolution (LMIR) in the MetS model compared to healthy mice following AgNP exposure. Statin treatment inhibited enhanced inflammatory responses as well as alterations in LMIR observed in the MetS model due to AgNP exposure. Taken together our data suggests that MetS exacerbates the acute toxicity induced by AgNPs exposure possibly via a disruption of LMIR leading to enhanced pulmonary inflammation.

Dataset Information

ISU201 enhances the resolution of airway inflammation in a mouse model of an acute exacerbation of asthma.

Publications

ISU201 enhances the resolution of airway inflammation in a mouse model of an acute exacerbation of asthma.

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