A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase.

RATIONALE

Cellular redox homeostasis altered by excessive production of reactive oxygen species (ROS) and weakening of the antioxidant defense leads to oxidative stress. Oxidative stress is characterized as a decrease in glutathione/glutathione disulfide (GSH/GSSG) and the triggering of a number of the redox-sensitive signaling cascades. Recent studies have demonstrated that ROS play an important role in the pathogenesis of airway inflammation and hyperresponsiveness.

OBJECTIVES

Here we characterized for the first time the protective properties of a new hydrophobic thiol compound, N-acetyl cysteine proline cysteine amide (CB3), in allergic airway diseases.

METHODS

We used ovalbumin (OVA)-inhaled mice to evaluate the role of CB3 as an antiinflammatory reagent and to determine its molecular signaling activity in allergic airways.

MEASUREMENTS AND MAIN RESULTS

The administration of CB3 (1-50 mg/kg) to OVA-inhaled mice restored the decreased GSH levels, enhanced IL-10 expression, and significantly reduced the increase of Th2 cytokines and OVA-specific IgE. CB3 decreased the number of inflammatory cells and airway hyperresponsiveness in the lungs. We also found that the administration of CB3 dramatically decreased the nuclear translocation of the nuclear factor-κB (NF-κB) and the phosphorylation of p38 mitogen-activated protein kinases (MAPKs) in lungs after OVA inhalation. In addition, allergen-induced airway inflammation and hyperresponsiveness were substantially reduced by the administration of inhibitors of NF-κB and p38 MAPK, BAY 11-7085, and SB 239063, respectively.

CONCLUSIONS

These results suggest that CB3 attenuates allergic airway disease by up-regulation of GSH levels as well as inhibition of NF-κB and p38 MAPK activity.