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Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma  Sarah K. Norton, PhD, Dayanjan S. Wijesinghe,

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Presentation on theme: "Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma  Sarah K. Norton, PhD, Dayanjan S. Wijesinghe,"— Presentation transcript:

1 Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma  Sarah K. Norton, PhD, Dayanjan S. Wijesinghe, PhD, Anthony Dellinger, BS, Jamie Sturgill, PhD, Zhiguo Zhou, PhD, Suzanne Barbour, PhD, Charles Chalfant, PhD, Daniel H. Conrad, PhD, Christopher L. Kepley, PhD, MBA  Journal of Allergy and Clinical Immunology  Volume 130, Issue 3, Pages e2 (September 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 A novel FD, C70-tetraglycolate, inhibits airway inflammation and bronchoconstriction in a murine model of asthma. A, Fullerene TGA consists of 4 glycolic acids covalently bonded to the fullerene C70 core, creating a water-soluble molecule. B, Schematic of the OVA challenge acute asthma model. Allergic lung inflammation was induced by means of intraperitoneal (i.p.) sensitization with OVA followed by 3 intranasal (i.n.) OVA challenges. Tetraglycolate was administered intranasally every 3 days starting on day −1. C, After OVA intranasal challenge, BALF and lung tissues were collected. The total number of cells (left) was counted with trypan blue and the total number of eosinophils (right) in BALF cells was counted by using Hema 3. Nonsensitized (NS) controls are shown for reference (n = 6-10 animals per group). *P < .05 or **P < .001, as determined by using the Student t test. D and E, TGA-treated mice survived to a higher dose of methacholine (Fig 1, D) and were less responsive to aerosolized methacholine compared with PBS-treated animals (Fig 1, E). F and G, In separate experiments using this model, lung tissues were fixed, sectioned, and stained with hematoxylin and eosin (Fig 1, F) and periodic acid–Schiff (Fig 1, G). Representative photographs show cellular infiltration into the airways of OVA-sensitized mice treated with PBS or TGA. Arrows indicate areas of inflammation (magnification × 10) and eosinophils (magnification × 100). Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 1 A novel FD, C70-tetraglycolate, inhibits airway inflammation and bronchoconstriction in a murine model of asthma. A, Fullerene TGA consists of 4 glycolic acids covalently bonded to the fullerene C70 core, creating a water-soluble molecule. B, Schematic of the OVA challenge acute asthma model. Allergic lung inflammation was induced by means of intraperitoneal (i.p.) sensitization with OVA followed by 3 intranasal (i.n.) OVA challenges. Tetraglycolate was administered intranasally every 3 days starting on day −1. C, After OVA intranasal challenge, BALF and lung tissues were collected. The total number of cells (left) was counted with trypan blue and the total number of eosinophils (right) in BALF cells was counted by using Hema 3. Nonsensitized (NS) controls are shown for reference (n = 6-10 animals per group). *P < .05 or **P < .001, as determined by using the Student t test. D and E, TGA-treated mice survived to a higher dose of methacholine (Fig 1, D) and were less responsive to aerosolized methacholine compared with PBS-treated animals (Fig 1, E). F and G, In separate experiments using this model, lung tissues were fixed, sectioned, and stained with hematoxylin and eosin (Fig 1, F) and periodic acid–Schiff (Fig 1, G). Representative photographs show cellular infiltration into the airways of OVA-sensitized mice treated with PBS or TGA. Arrows indicate areas of inflammation (magnification × 10) and eosinophils (magnification × 100). Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 2 Tetraglycolate dampens cellular infiltration, eosinophilia, and inflammatory cytokine levels in a murine model of established asthma. A, An established asthma model was used, as described in the Methods section. After the first set of intranasal (i.n.) OVA challenges, mice began treatment with 20 μg of TGA every 3 days. i.p., Intraperitoneal. B, Cells in BALF were stained with the Hema 3 stain set. Inflammatory cells in BALF were counted, and eosinophils are represented as a percentage of total inflammatory cells. C, Cytokine levels in BALF were measured with a multiplex cytokine assay. D, Lung tissue was sectioned and stained with hematoxylin and eosin. Arrows indicate airways. Representative photographs are shown (n = 6-12 mice per group). *P < .05, as determined by using the Student t test when variances were normal or the Mann-Whitney test in the case of unequal variances. NS, Nonsensitized. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 3 Tetraglycolate significantly reduces inflammatory cytokine, eicosanoid, and serum IgE levels. Asthma induction and fullerene treatment is described in Fig 1, B. A, Inflammatory cytokine levels were measured in BALF by using a multiplex cytokine assay. B, Serum was collected after OVA intranasal challenge and total IgE levels were measured by using ELISA. C, Levels of 11,12-EET were measured in BALF by means of mass spectrometry. These values were standardized by calculating the fold change relative to nonsensitized (NS) animals to account for variation between experiments (n = 6-9 mice per group). D, Human lung MCs were pretreated with 10 μg/mL TGA overnight and activated 16 hours later with anti-FcεRI antibodies (1 μg/mL). Gene microarray was performed,14 and relative gene expression of CYP1B1 is shown. Each condition was performed in triplicate. *P < .05, as determined by using the Student t test when variances were normal or the Mann-Whitney test in the case of unequal variances. E, Epoxygenases reduce degranulation from human lung MCs after anti-FcεRI activation. Cells were cultured with fixed concentrations of the indicated EET or vehicle control (VC; ethanol, 40 μmol/L), washed, and stimulated for 20 minutes with optimal concentrations of anti-FcεRI antibodies (3B4; 1 mg/mL). Cells were centrifuged, and β-hexosaminidase release and cytokine production were determined. The data shown are the average of 2 separate experiments performed in triplicate, with means ± SEs. The asterisk indicates statistical significance compared with the vehicle control. F, TGA inhibits IgE production by cultured B cells. B cells were incubated with or without TGA before being activated with IL-4/anti-CD40 for 8 days. Cells were centrifuged, and IgE levels in the supernatants were measured by using ELISA. B-cell viability was assessed by using propidium iodide staining of dead cells. The percentage of propidium iodide–positive cells was assessed by using a flow cytometer for the first 5 days of incubation, after which viability was dramatically reduced in all groups. Experiments were performed at least 3 times in duplicate, and representative data are shown. There are no toxic effects on these cells compared with B cells that are left untreated or those treated with the nontoxic antioxidant ascorbic acid. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 4 Inhibiting the induction of 11,12-EET by TGA restores the asthma phenotype. Effects of the inhibitor of EET, PPOH, on airway inflammation and bronchoconstriction were assessed. A, Cells in BALF were stained with the Hema 3 stain set. Inflammatory cells in BALF were counted, and each cell type is shown as a percentage of total inflammatory cells. B, Airway resistance (RL) was measured in response to increasing doses of methacholine. C, Representative lung sections are stained with hematoxylin and eosin. Arrows indicate airways. Bar = 100 μm. N = 6 mice per group. *P < .05. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E1 Mice have no evident toxicity after long-term treatment with TGA. A, Levels of the liver enzymes AST and ALT were measured in sera of TGA-treated animals by using ELISA. B, Creatinine levels were measured in sera of TGA-treated animals by using ELISA. N = 6 animals per group. NS, Not significant. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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