Epoxyeicosatrienoic acids are involved in the C(70) fullerene derivative-induced control of allergic asthma.
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 (C(70)-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.


CONCLUSIONS
The inhibitory capabilities of TGA reported here suggest that FDs might be used a platform for developing treatments for asthma.
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
Sarah K
SK
Norton
Dayanjan S
DS
Wijesinghe
Anthony
A
Dellinger
Jamie
J
Sturgill
Zhiguo
Z
Zhou
Suzanne
S
Barbour
Charles
C
Chalfant
Daniel H
DH
Conrad
Christopher L
CL
Kepley
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D004802:Eosinophilia / Q000188:drug therapy; D005260:Female; D037741:Fullerenes / Q000494:pharmacology* / Q000627:therapeutic use; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D037741:Fullerenes; C069836:fullerene C70; D007073:Immunoglobulin E; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid