fullerene-c70 and Asthma

Water-soluble fullerenes can be engineered to regulate activation of mast cells (MC) and control MC-driven diseases in vivo. To further understand their anti-inflammatory mechanisms a C70-based fullerene conjugated to four myo-inositol molecules (C70-I) was examined in vitro for its effects on the signaling pathways leading to mediator release from human lung MC. The C70-I fullerene stabilizes MC and acts synergistically with long-acting β2-adrenergic receptor agonists (LABA) to enhance inhibition of MC mediator release through FcεRI-simulation. The inhibition was paralleled by the upregulation of dual-specificity phosphatase one (DUSP1) gene and protein levels. Concomitantly, increases in MAPK were blunted in C70-I treated cells. The increase in DUSP1 expression was due to the ability of C70-I to prevent the ubiquitination and degradation of DUSP1. These findings identify a mechanism of how fullerenes inhibit inflammatory mediator release from MC and suggest they could potentially be an alternative therapy for steroid resistant asthmatics.. This study investigates the role and mechanism of action of fullerenes in deactivating mast cell-based inflammation, paving the way to the development of a novel, non-steroid therapy in reactive airway disease.

Topics: Anti-Inflammatory Agents; Asthma; Cell Degranulation; Fullerenes; Humans; Lung; Mast Cells; Steroids

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.. 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.. 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.. 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.. The inhibitory capabilities of TGA reported here suggest that FDs might be used a platform for developing treatments for asthma.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Asthma; Bronchoconstriction; Eosinophilia; Female; Fullerenes; Immunoglobulin E; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL