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 FcεRI 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.
|Journal||Journal of Allergy and Clinical Immunology|
|State||Published - Sep 2012|
Bibliographical noteFunding Information:
Supported by grants 1R01GM083274-01C and R21 ESO15696-01A1 to C.L.K. , grant 1U19AI077435 -project 2 to D.H.C. , and American Heart Association predoctoral award no. 10PRE4170025 to S.K.N. Microscopy was performed at the VCU Department of Neurobiology and Anatomy microscopy facility, which is supported in part with funding from a National Institutes of Health/National Institute of Neurological Disorders and Stroke center core grant 5P3ONS047463 .
Disclosure of potential conflict of interest: S. K. Norton has received research support from the National Institutes of Health (NIH) and the American Heart Association . A. Dellinger, S. Barbour, D. H. Conrad, and C. L. Kepley have received research support from the NIH. The rest of the authors declare that they have no relevant conflicts of interest.
- Fullerene derivative
- airway inflammation
ASJC Scopus subject areas
- Immunology and Allergy