Arsenic trioxide, a potent inhibitor of NF-kappaB, abrogates allergen-induced airway hyperresponsiveness and inflammation.
BACKGROUND
Overactivation of nuclear factor kappaB (NF-kappaB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. NF-kappaB repression by arsenic trioxide (As2O3) contributes to apoptosis of eosinophils (EOS) in airways. Here we provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IkappaBalpha, an NF-kappaB inhibitory protein, and decreases the airway hyperresponsiveness.


METHODS
Using a murine model of asthma, the airway hyperresponsiveness was conducted by barometric whole-body plethysmography. Airway eosinophilia, OVA-specific IgE in serum, and chemokine eotaxin and RANTES (regulated upon activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid were measured by lung histology, Diff-Quick staining, and ELISA. Chemokine-induced EOS chemotactic activity was evaluated using EOS chemotaxis assay. Electrophoretic mobility shift assay and Western blot analysis were performed to assess pulmonary NF-kappaB activation and IkappaBalpha expression, respectively.


RESULTS
As2O3 attenuated the allergen-induced serum IgE, chemokine expression of eotaxin and RANTES, and the EOS recruitment in bronchoalveolar lavage fluid, which is associated with an increased IkappaBalpha expression as well as a decreased NF-kappaB activation. Also, As2O3 suppressed the chemotaxis of EOS dose-dependently in vitro. Additionally, As2O3 significantly ameliorated the allergen-driven airway hyperresponsiveness, the cardinal feature underlying asthma.


CONCLUSIONS
These findings demonstrate an essential role of NF-kappaB in airway eosinophilia, and illustrate a potential dissociation between airway inflammation and hyperresponsiveness. As2O3 likely exerts its broad anti-inflammatory effects by suppression of NF-kappaB activation through augmentation of IkappaBalpha expression in asthma.
Zhou
Lin-Fu
LF
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China. lfzhou@njmu.edu.cn
Zhu
Yi
Y
Cui
Xue-Fan
XF
Xie
Wei-Ping
WP
Hu
Ai-Hua
AH
Yin
Kai-Sheng
KS
D000485:Allergens; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D001991:Bronchitis / Q000276:immunology / Q000517:prevention & control; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology*; D010047:Ovalbumin; D010087:Oxides / Q000008:administration & dosage*; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000517:prevention & control
D000485:Allergens; D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D010047:Ovalbumin; D000077237:Arsenic Trioxide