Bu-Shen-Yi-Qi formula ameliorates airway remodeling in murine chronic asthma by modulating airway inflammation and oxidative stress in the lung.

Bu-Shen-Yi-Qi formula (BSYQF) could suppress chronic airway inflammation according to previous studies. However, there is relatively little direct experimental evidence to evaluate the effects of BSYQF treatment on airway remodeling in chronic asthma. Recent evidence suggests that oxidative stress is involved in airway inflammation and airway remodeling in chronic asthma. BSYQF which includes various of chemical components having antioxidant effects, could be beneficial in attenuating airway remodeling in chronic asthma. The purpose of this study was to elucidate the effect of BSYQF treatment on airway remodeling and investigate its potential mechanisms in chronic asthma. To develop the murine models of chronic asthma, BALB/c mice were sensitized and challenged to ovalbumin for 8 weeks. BSYQF (5, 10, 20 g raw herbs/kg body weight) or tiotropium bromide (0.1 mM) were administered orally and intranasal instillation, respectively. The effect of BSYQF on pulmonary inflammation and remodeling was evaluated. The parameters of oxidative stress in the lung were analyzed. BSYQF treatment reduced airway hyperresponsiveness (AHR), Th2 response including IL-4, IL-13, and OVA-specific IgE and IgG1, transforming growth factor-β (TGF-β), vascular endothelium growth factor (VEGF), airway inflammation and airway remodeling including smooth muscle thickening and peribronchial collagen deposition. As for oxidative stress, BSYQF treatment reduced reactive oxygen species (ROS), Malondialdehyde (MDA), NO, and the expression of inducible nitric oxide synthase (iNOS), but increased significantly glutathione (GSH) /Oxidized glutathione(GSSH) ratios in the lung, restored mitochondrial ultrastructural changes of bronchial epithelia and ATP levels in the lung. In summary, this study suggested that BSYQF treatment ameliorated airway remodeling and alleviated asthmatic features in chronic asthma models. Anti-inflammatory and antioxidant effect of BSYQF may explain why BSYQF has effects on preventing airway remodeling.

Cui J ，Xu F ，Tang Z ，Wang W ，Hu LL ，Yan C ，Luo Q ，Gao H ，Wei Y ，Dong J ... -  《-》

Bu-Shen-Yi-Qi formulae suppress chronic airway inflammation and regulate Th17/Treg imbalance in the murine ovalbumin asthma model.

Bu-Shen-Yi-Qi formulae (BSYQF) are frequently used in the treatment of chronic inflammatory diseases in the respiratory system in traditional Chinese medicine (TCM). However, the regulatory effect of BSYQF on T helper 17 (Th17) and regulatory T (Treg) cells in murine ovalbumin (OVA) asthma model remains poorly understood. In the present study, we sought to determine the effect of high-performance liquid chromatography/mass spectrometry (HPLC/MS) standardized BSYQF on chronic airway inflammation and Th17/Treg imbalance in the murine OVA asthma model. The murine asthma model was induced by OVA sensitization and challenge and BSYQF was oral administrated. 24h after last OVA exposure, airway hyperresponsiveness (AHR) to methacholine (Mch) was assessed, and inflammatory cell counts and classification in bronchoalveolar lavage fluid (BALF) were analysed. Histopathological evaluation of the lung tissue was performed by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. Th17 and Treg associated cytokine levels in serum and BALF as well as transcription factors expression in the lung tissue were measured by ELISA, Bio-Plex and western blot assay. We also analysed the CD4(+)RORγt(+) and CD4(+)Foxp3(+) T cells in BALF and spleen by flow cytometric analysis. Our results demonstrated that oral administration of BSYQF inhibited the markedly increased AHR and lung inflammation (p<0.05), resulted in a dramatic reduction in total inflammatory cells as well as neutrophils (Neu), lymphocytes (Lym), monocytes (Mon), eosinophils (Eos) and basophils (Bas) of OVA-induced asthmatic mice (p<0.05). Furthermore, BSYQF treatment caused a distinct reduction in IL-6, IL-10 and IL-17A levels in serum (p<0.05), and induced a significant improvement in IL-6 and IL-10 as well as a marked decrease in TGF-β1 and IL-17A levels in BALF of OVA-induced asthmatic mice (p<0.05). Mice in BSYQF treated groups also had decreased RORγt and increased Foxp3 expression in the lung tissue (p<0.05). Flow cytometry analysis revealed that CD4(+)RORγt(+) T cells elevated markedly and CD4(+)Foxp3(+) T cells decreased prominently in BALF and spleen in murine OVA asthma model (p<0.05), and BSYQF and DEX treatment lead to an obvious reduction in CD4(+)RORγt(+) T cells in BALF (p<0.05) but not in spleen. BSYQF and DEX treatment resulted in an obvious elevation in CD4(+)Foxp3(+) T cells in BALF and spleen (p<0.05). Collectively, these results demonstrated that BSYQF could suppress chronic airway inflammation and regulate Th17/Treg imbalance by inhibition of Th17 and enhancement of Treg functions in the murine OVA asthma model, which may help to elucidate the underlying regulatory mode of BSYQF on asthma treatment.

Wei Y ，Luo QL ，Sun J ，Chen MX ，Liu F ，Dong JC ... -  《-》

BuShenYiQi Formula strengthens Th1 response and suppresses Th2-Th17 responses in RSV-induced asthma exacerbated mice.

The prevalence of allergic asthma has been increased rapidly in recent years. About 20% of all these sufferers have experienced asthma exacerbation. Although corticosteroids and β-agonists therapy improves serious asthma symptoms, they can׳t completely cure these allergic diseases. BuShenYiQi Formula (BSYQF) has been widely used to treat bronchial asthma and its exacerbation for decades in Huashan Hospital of Fudan University, China. Nevertheless, the mechanisms of BSYQF' anti-asthmatic effects haven׳t been fully elucidated. In this study, we evaluated the involvement of Th1, Th2 and Th17 cells in the anti-asthmatic effects of BSYQF in Respiratory Syncytial Virus (RSV)-induced asthma exacerbated mice. BALB/c mice were challenged with ovalbumin (OVA), followed by RSV infections for establishment of asthma exacerbated model. Airway hyperresponsiveness (AHR) was examined by direct airway resistance analysis. Bronchoalveolar lavage fluid (BALF) was assessed for inflammatory cell counts and secreted levels of cytokines. Lung tissues were detected for inflammatory cell infiltration and mucus hypersecretion. Subsequently, CD4(+)T cells and alveolar macrophages were sorted and purified from mice lungs in different groups. CD4(+)T cell subpopulations including the expression levels of important transcription factors in T lymphocyte polarization were examined. In asthma exacerbation group, the purified CD4(+)T cells and macrophages were co-cultured, and the changes of co-cultured cells with BSYQF treatment were further analyzed in vitro. BSYQF significantly attenuated airway hyperresponsiveness and inhibited inflammatory cell infiltration, especially for excessive infiltration of eosinophils and neutrophils. Histopathological analysis showed that BSYQF could suppress airway inflammation and RSV replication. The decreases of antigen-specific IgE, IL-4, IL-5, IL-6, IL-17a and increases of IFN-γ, IL-12 were observed in BALF, lung homogenate or serum after BSYQF treatment. We further confirmed that BSYQF could down-regulate Th2-Th17 cell proportions with lower expressions of GATA3, STAT6 and RORγT, and up-regulate Th1 cell proportion with higher expression of T-bet. And as a result of strengthened Th1-response, activated macrophages were also observed by remarkable enhancement of signature gene expressions and phagocytosis. BSYQF can significantly attenuate RSV-induced asthma exacerbation. These effects may be mediated at least partially by regulating the balance between Th1 and Th2-Th17 responses.

Wang J ，Wu J ，Kong L ，Nurahmat M ，Chen M ，Luo Q ，Li B ，Wu X ，Dong J ... -  《-》

Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model.

Mabalirajan U ，Aich J ，Leishangthem GD ，Sharma SK ，Dinda AK ，Ghosh B ... -  《-》

Herbal decoction Divya-Swasari-Kwath attenuates airway inflammation and remodeling through Nrf-2 mediated antioxidant lung defence in mouse model of allergic asthma.

Asthma is a chronic respiratory disease orchestrated by immune and structural cells. Identification of novel therapeutic strategies are needed for asthma due to the limitations of existing therapies. We have validated the anti-inflammatory, anti-asthmatic and immunomodulatory therapeutic properties of herbal decoction, Divya-Swasari-Kwath (DSK) using mouse model of ovalbumin (OVA) induced allergic asthma. HPLC analysis identified the presence of Rutin, Glycyrrchzin, Gallic acid, Cinnamic acid, Chlorogenic acid, Caffeic acid and Piperine as bioactive herbal metabolites in DSK. Therapeutic treatment with herbal decoction DSK significantly alleviated the pathological features of allergic asthma including inflammatory cell accumulation in Broncho-Alveolar Lavage (BAL) fluids, specifically lymphocytes and eosinophils, lung inflammation, oxidative stress, airway remodelling, and pro-inflammatory cytokine levels. H&E analysis of lung tissue sections identified attenuated inflammatory cell infiltration and thickening of bronchial epithelium by DSK. PAS staining and MT staining identified decrease in OVA-induced mucus hyper secretion and peri-bronchial collagen deposition respectively, upon DSK treatment. Treatment with DSK increased the mRNA expression of antioxidative defence gene Nrf-2 and its downstream target genes HO-1 and NQO-1. In the same line, biochemical analysis for the markers of oxidative/antioxidant system confirmed the restoration of activity of Catalase, GPx, SOD and EPO and the levels of GSH, GSSG, MDA and Nitrite in whole lungs. In line with PAS staining, DSK treatment decreased the OVA-induced expression of Muc5AC and Muc5B genes. DSK treatment reduced the steady state mRNA expression levels of IL-6, IL-1β, TNF-α, IL-4, -5, -33, IFN-γ in whole lung; and IL-6, TNF-α and IL-1β protein levels in BALF. Collectively, our results suggest that herbal decoction DSK is effective in protecting against allergic airway inflammation and remodelling by regulating anti-oxidant mechanisms. We postulate that DSK could be the potential therapeutic option for allergic asthma management.

Balkrishna A ，Solleti SK ，Singh H ，Verma S ，Sharma N ，Nain P ，Varshney A ... -  《-》