ORMDL3 knockdown in the lungs alleviates airway inflammation and airway remodeling in asthmatic mice via JNK1/2-MMP-9 pathway.

Orosomucoid-like protein 3 (ORMDL3) is a common mutation in many asthma patients and its effects on the specific pathogenesis of asthma are still unclear. Therefore, in this study, we used a mouse that specifically knockout the mouse ORDML3 gene to further study the mechanism. We used ovalbumin (OVA) to induce asthma in wild-type mice and ORMDL3 knockout mice. Lung ventilation resistance, airway inflammation, mucus hypersecretion, collagen deposition, the levels of inflammatory factors and the expression of ORDML3 and JNK1/2-MMP-9 pathway were detected. The results showed that ORMDL3 gene was highly expressed in clinical asthmatic children and mouse asthma model. Knocking down the ORMDL3 gene in the lung tissue of asthmatic mice can reduce airway hyperresponsiveness, airway inflammation, mucus secretion, and collagen deposition around the airway. After knocking down the lung tissue of mice, the IL-4, IL-5 and IL-13 concentrations in broncho alveolar lavage fluid of asthmatic mice were significantly decreased, and the activation of JNK1/2-MMP-9 pathway was inhibited in mouse lung tissue. Collectively, our results demonstrate that the ORMDL3 gene may aggravate asthma symptoms by activating the JNK1/2-MMP-9 pathway, which indicates that the ORMDL3 gene may be the key molecule for the next step of asthma targeted therapy.

Wang H ，Liu Y ，Shi J ，Cheng Z ... -  《-》

Inhibition of airway inflammation, hyperresponsiveness and remodeling by soy isoflavone in a murine model of allergic asthma.

Epidemiologic studies have associated higher dietary consumption of soy isoflavones with decreased self-report of cough and allergic respiratory symptoms, but the pharmacodynamic effects of soy isoflavone on asthmatic model have not been well-described. Here, we hypothesized that soy isoflavone may have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for inflammatory cell counts, and for cytokine levels. Lung tissues were examined for cell infiltration, mucus hypersecretion and airway remodeling, and for the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Oral administration of soy isoflavone significantly reduced ovalbumin-induced airway hyperresponsiveness to intravenous methacholine, and inhibited ovalbumin-induced increases in eosinophil counts. RT-PCR analysis of whole lung lysates revealed that soy isoflavone markedly suppressed ovalbumin-induced mRNA expression of eotaxin, interleukin(IL)-5, IL-4 and matrix metalloproteinase-9, and increased mRNA expression of interferon (IFN)-γ and tissue inhibitor of metalloproteinase-1 in a dose-dependent manner. Soy isoflavone also substantially recovered IFN-γ/IL-4 (Th1/Th2) levels in bronchoalveolar lavage fluid. In addition, histologic studies showed that soy isoflavone dramatically inhibited ovalbumin-induced lung tissue eosinophil infiltration, airway mucus production and collagen deposition in lung tissues. Our findings suggest that soy isoflavone as nutritional supplement may provide a novel means for the treatment of airway inflammatory disease.

Bao ZS ，Hong L ，Guan Y ，Dong XW ，Zheng HS ，Tan GL ，Xie QM ... -  《-》

Targeted inhibition of Six1 attenuates allergic airway inflammation and remodeling in asthmatic mice.

Asthma is an inflammatory disease of the airways, characterized by lung eosinophilia, mucus hypersecretion by goblet cells and airway hyperresponsiveness to inhaled allergens. The purpose of this study was to evaluate the effects of Six1 on airway inflammation and remodeling and the underlying mechanisms in a murine model of chronic asthma. Female BALB/c mice were randomly divided into four groups: phosphate-buffered saline control, ovalbumin (OVA)-induced asthma group, OVA+siNC and OVA+siSix1. In this mice model, Six1 expression level was significantly elevated in OVA-induced asthma of mice. Additionally, downregulation of Six1 dramatically decreased OVA-challenged inflammation, infiltration, and mucus production. Moreover, silencing of Six1 resulted in decreased levels of immunoglobulin E and inflammatory mediators and reduced inflammatory cell accumulation, as well as inhibiting the expression of important mediators including matrix metalloproteinase MMP-2 and MMP-9, which is related to airway remodeling. Further analysis indicated that silencing of Six1 can significantly inhibit NF-kB pathway activation in the lungs. .In conclusion, these findings indicated that the downregulation of Six1 effectively inhibited airway inflammation and reversed airway remodeling, which suggest that Six1 represents a promising therapeutic strategy for human allergic asthma.

Yang ZC ，Yi MJ ，Shan YC ，Wang C ，Ran N ，Jin LY ，Fu P ，Feng XY ，Xu L ，Qu ZH ... -  《-》

ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway.

Yu F ，Sun Y ，Yu J ，Ding Z ，Wang J ，Zhang L ，Zhang T ，Bai Y ，Wang Y ... -  《-》

Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma.

Yao Y ，Zeng QX ，Deng XQ ，Tang GN ，Guo JB ，Sun YQ ，Ru K ，Rizzo AN ，Shi JB ，Fu QL ... -  《PLoS One》