Effects And Mechanisms Of Deguelin In Asthmatic Mice With Allergic Airway Inflammation

Asthma is one of the most common respiratory diseases all over the world.It is a chronic respiratory disease characterized by airway inflammation and airway hyperresponsiveness,which can affect all age groups,resulting in a substantial economic burden on both patients and society.The pathogenesis of asthma is very complicated,including imbalance of different lymphocytes subgroup,eosinophilic airway infiltration,alveolar macrophage dysfunction and overexpression of a variety of cytokines and immuboglobulin.While there are lots of researches reported the new progress and understanding of the mechanism in asthma,there is still lack of effective treatment methods to control the refractory asthma and related inflammatory responses.Recently,effects of traditional Chinese herbals have shed lights on the treatment of asthma.Deguelin,a constituent of the Leguminosae family,exhibits anti-proliferative and anti-inflammatory activities in cancer mice models via inhibiting phosphatidylinositol 3-kinases pathway.Meanwhile,deguelin can effectively inhibit the activity of the nuclear factor-κB(NF-κB)pathway,suggesting potential anti-inflammatory effects according to the literature.Thus,the effects and mechanisms of deguelin in allergic airway inflammation are still need to be illustrated.In our study,we firstly built up an acute asthmatic mice model by ovalbumin sensitization and challenge.Then,deguelin or dexamethasone was given by intraperitoneal injections to mice.Bronchoalveolar Lavage Fluid collection and differential cell counts were performed to investigate inflammatory cell infiltration.Hematein&Eosin and Periodic Acid-Schiff staining were performed to show inflammatory cell infiltration and mucus production.A whole-body plethysmography was used to evaluate the airway hyperresponsiveness in mice.Then,we performed enzyme-linked immunosorbent assay to analysis serum immunoglobulin and cytokine.And we further performed RT-PCR to analysis T helper cell(Th)2 cytokine expression and inflammatory gene expression.We performed flow cytometry to investigate expression of thymic stromal lymphopoietin.Furthermore,we treated human bronchial epithelial cells(BEAS-2B)with deguelin,then performed cell viability assay to evaluate cytotoxicity,and reverse transcription-polymerase chain reaction(RT-PCR)to analysis inflammatory gene expression.Finally,we treated BEAS-2B cells with deguelin or BAY 11-7082 or deguelin plus BAY 11-7082,and performed western blot to explore effects and mechanisms of deguelin on NF-κB activation.Our results demonstrated that in asthmatic mice,deguelin effectively reduced ovalbumin-induced inflammatory cell recruitment,decreased lung tissue inflammation and mucus production,suppressed airway hyperresponsiveness,inhibited serum immunoglobulin and Th2 cytokine levels in a dose-dependent manner in airways of asthmatic mice.In addition,we also found that deguelin reduced inflammatory gene.expression both in vivo and in vitro,which were closely associated with activation of the NF-κB signaling pathway,and enhanced the ability of inhibitor of κB a(IκBα)to maintain NF-κB in an inactive form in the cytoplasm,suppressing the phosphorylation of both IKBa and p65,and preventing TNF-a induced translocation of p65 to the nucleus.Moreover,deguelin attenuated TNF-a induced NF-κB activation more effectively when combined with a NF-κB inhibitor,BAY 11-7082,than administered alone.In conclusion,our research indicates that deguelin attenuates allergic airway inflammation via inhibition of NF-κB pathway,and may act as an effective therapeutic agent for patients with allergic airway inflammation.