Arsenic trioxide, a potent inhibitor of NF-kappaB, abrogates allergen-induced airway hyperresponsiveness and inflammation.

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. 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. 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. 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 LF ，Zhu Y ，Cui XF ，Xie WP ，Hu AH ，Yin KS ... -  《RESPIRATORY RESEARCH》

Effects of (±)-praeruptorin A on airway inflammation, airway hyperresponsiveness and NF-κB signaling pathway in a mouse model of allergic airway disease.

The root of Peucedanum praeruptorum Dunn is a traditional Chinese medicine commonly used to treat asthma in China. (±)-praeruptorin A (PA) is the most abundant constituent of P. praeruptorum Dunn, the effects of which on asthma were investigated using a murine model of allergic airway disease. BALB/c mice were sensitized and challenged by ovalbumin to induce airway inflammation. PA was administered intragastrically before every OVA challenge. Airway responsiveness was measured by a lung function analysis system. The number of total leukocytes in bronchoalveolar lavage fluid was counted using a hemocytometer, and differential cell counts were determined using Diff-Quick-stained smears. Histopathology of lung tissue was analyzed by hematoxylin-eosin and Congo red staining. Levels of inflammatory mediators in bronchoalveolar lavage fluid and immunoglobulins in serum were measured by enzyme-linked immunosorbent assay. The expression of pulmonary eotaxin was detected by immunohistochemistry and reverse transcription polymerase chain reaction. The activation of NF-κB was evaluated by electrophoretic mobility shift assay and western blot analysis. Compared with model group, PA significantly reduced airway hyperresponsiveness and airway eosinophilic inflammation, improved pathologic lesion of the lungs, reduced levels of interleukin (IL)-4, IL-5, IL-13 and LTC₄ in bronchoalveolar lavage fluid and immunoglobulin (Ig) E in serum, and inhibited eotaxin protein and mRNA expression, IκBα degradation, NF-κB nuclear translocation, NF-κB DNA-binding activity and RelA/p65 phosphorylation in lung, which suggested that PA can significantly suppress OVA-induced airway inflammation and airway hyperresponsiveness in mice, showing great therapeutic potential for the treatment of allergic asthma.

Xiong Y ，Wang J ，Wu F ，Li J ，Zhou L ，Kong L ... -  《-》

Five-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates poly (I:C)-induced airway inflammation in a murine model of asthma.

Kim TB ，Kim SY ，Moon KA ，Park CS ，Jang MK ，Yun ES ，Cho YS ，Moon HB ，Lee KY ... -  《CLINICAL AND EXPERIMENTAL ALLERGY》

NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation.

The NF-kappa B/Rel family of transcription factors induces many genes involved in immune and inflammatory responses. Mice with germline deletions of individual NF-kappa B/Rel subunits have different phenotypes, suggesting that the NF-kappa B/Rel transcription factors have different functions. We tested whether c-Rel promotes allergic asthma using a murine model of allergen-induced pulmonary inflammation and airway hyperresponsiveness. Our investigation focused on c-Rel, which is expressed in lymphoid cells and is important for lymphocyte activation. In response to allergen sensitization and challenge, c-Rel-deficient mice did not develop increases in pulmonary inflammation, bronchoalveolar lavage fluid eosinophilia, or total serum IgE. c-Rel deficiency also prevented the induction of airway hyperresponsiveness. Allergen-treated wild-type mice had increased DNA binding to an NF-kappa B consensus site. Chemokine expression was altered in allergen-treated c-Rel-deficient mice. Monocyte chemoattractant protein-1, which is regulated by NF-kappa B, was decreased in allergen-treated c-Rel-deficient mice relative to wild-type controls. The increase in NF-kappa B/Rel transcription factors after allergen challenge in wild-type mice and the decrease in allergen reactivity found in c-Rel-deficient mice indicate that c-Rel promotes allergic inflammation. Alteration of pulmonary chemokine expression in c-Rel-deficient mice may inhibit allergen-induced pulmonary inflammation and airway hyperresponsiveness.

Donovan CE ，Mark DA ，He HZ ，Liou HC ，Kobzik L ，Wang Y ，De Sanctis GT ，Perkins DL ，Finn PW ... -  《JOURNAL OF IMMUNOLOGY》

Caffeic acid phenethyl ester attenuates allergic airway inflammation and hyperresponsiveness in murine model of ovalbumin-induced asthma.

Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of propolis, which has several interesting biological properties, including antioxidant and anti-inflammatory; however, its anti-allergic effects are poorly understood. The objective of this study was to determine whether treatment with CAPE results in significant inhibition of asthmatic reactions in a mouse model. Mice sensitized and challenged with ovalbumin (OVA) had the following typical asthmatic reactions: an increase in the number of eosinophils in bronchoalveolar lavage (BAL) fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways, and airway luminal narrowing; the development of airway hyperresponsiveness (AHR); the presence of tumor necrosis factor-alpha (TNF-alpha) and Th2 cytokines, including IL-4 and IL-5, in the BAL fluid; and the presence of allergen-specific IgE in the serum. Five successive intraperitoneal administrations of CAPE before the last airway OVA challenge resulted in significant inhibition of characteristic asthmatic reactions. We determined that increased generation of reactive oxygen species (ROS) by inhalation of OVA was diminished via the administration of CAPE in BAL fluid, as well as nuclear factor-kappaB (NF-kappaB) DNA binding activity. These findings indicate that oxidative stress may have a crucial function in the pathogenesis of bronchial asthma, and that CAPE may be useful as an adjuvant therapy for the treatment of bronchial asthma.

Jung WK ，Lee DY ，Choi YH ，Yea SS ，Choi I ，Park SG ，Seo SK ，Lee SW ，Lee CM ，Kim SK ，Jeon YJ ，Choi IW ... -  《LIFE SCIENCES》