Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Christopher Kepley, Associate Professor (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/

Abstract: Background: Fullerenes are molecules being investigated for a wide range of therapeutic applications. We have shown previously that certain fullerene derivatives (FDs) inhibit mast cell (MC) function in vitro, and here we examine their in vivo therapeutic effect on asthma, a disease in which MCs play a predominant role. Objective: We sought to determine whether an efficient MC-stabilizing FD (C70-tetraglycolate [TGA]) can inhibit asthma pathogenesis in vivo and to examine its in vivo mechanism of action. Methods: Asthma was induced in mice, and animals were treated intranasally with TGA either simultaneously with treatment or after induction of pathogenesis. The efficacy of TGA was determined through the measurement of airway inflammation, bronchoconstriction, serum IgE levels, and bronchoalveolar lavage fluid cytokine and eicosanoid levels. Results: We found that TGA-treated mice have significantly reduced airway inflammation, eosinophilia, and bronchoconstriction. The TGA treatments are effective, even when given after disease is established. Moreover, we report a novel inhibitory mechanism because TGA stimulates the production of an anti-inflammatory P-450 eicosanoid metabolites (cis-epoxyeicosatrienoic acids [EETs]) in the lung. Inhibitors of these anti-inflammatory EETs reversed TGA inhibition. In human lung MCs incubated with TGA, there was a significant upregulation of CYP1B gene expression, and TGA also reduced IgE production from B cells. Lastly, MCs incubated with EET and challenged through FceRI had a significant blunting of mediator release compared with nontreated cells. Conclusion: The inhibitory capabilities of TGA reported here suggest that FDs might be used a platform for developing treatments for asthma. Abbreviations used: ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BALF, Bronchoalveolar lavage fluid; EET, Cis-epoxyeicosatrienoic acid; FD, Fullerene derivative; MC, Mast cell; OVA, Ovalbumin; PPOH, 6-(2-Propargyloxyphenyl) hexanoic acid; TGA, C70-tetraglycolate

Additional Information

Journal of Allergy and Clinical Immunology, 130(3), 761-769
Language: English
Date: 2012
Fullerene derivative, eicosanoids, asthma, airway inflammation, bronchoconstriction, allergy

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