Phosphatidylinositol 3-kinases pathway mediates lung caspase-1 activation and high mobility group box 1 production in a toluene-diisocyanate induced murine asthma model
Phosphatidylinositol 3-kinases pathway mediates lung caspase-1 activation and high mobility group box 1 production in a toluene-diisocyanate induced murine asthma model
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磷脂酰肌醇 3-激酶途径介导甲苯二异氰酸酯诱导的小鼠哮喘模型中肺 caspase-1 的激活和高迁移率族盒 1 的产生
DOI：
10.1016/j.toxlet.2015.04.011
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发表时间：
2015-07-02
影响因子：
3.5
通讯作者：
Cai, Shaoxi
中科院分区：
文献类型：
--
作者：
Liang, Junjie;Zhao, Haijin;Cai, Shaoxi
我们之前已经证明，在甲苯二异氰酸酯（TDI）诱导的小鼠哮喘模型中，下调HMGB1可减少气道中性粒细胞炎症，但HMGB1在肺中的调节方式仍不确定。本研究拟探讨PI3K信号通路是否介导tdi诱导哮喘模型中肺部HMGB1的产生，以及NLRP3炎性体和caspase-1在此过程中的可能作用。采用TDI致敏和刺激BALB/c小鼠，建立TDI诱导的哮喘模型。LY294002是一种PI3K特异性抑制剂，在每次给药前1小时气管内给予。本研究发现，LY294002可显著降低TDI致哮喘小鼠的气道过敏反应、气道中性粒细胞和嗜酸性粒细胞的浸润、血清IgE和颈淋巴细胞上清中IL-4的表达，同时抑制肺HMGB1的表达。同时，我们观察到TDI攻击后，裂解caspase-1和IL-1 β蛋白水平升高，肺部免疫反应性增加，LY294002均显著恢复。而NLRP3在肺组织中的蛋白表达和免疫分布不变。这些数据表明，在tdi诱导的小鼠哮喘模型中，PI3K介导肺caspase-1的激活和HMGB1的产生。2015爱思唯尔爱尔兰有限公司版权所有。
We have previously demonstrated that downregulating HMGB1 decreases airway neutrophil inflammation in a toluene-diisocyanate (TDI)-induced murine asthma model, yet how HMGB1 is regulated in the lung remains uncertain.In this study, we intended to explore whether PI3K signaling pathway mediates pulmonary HMGB1 production in TDI-induced asthma model and the possible roles of NLRP3 inflammasome and caspase-1 in this process.BALB/c mice were sensitized and challenged with TDI to establish a TDI-induced asthma model. LY294002, a specific inhibitor of PI3K, was given intratracheally 1 h before each challenge.Here we showed that airway hypersensitivity, airway infiltration of neutrophils and eosinophils, serum IgE and IL-4 in supernatant of cervical lymphocytes in TDI induced asthmatic mice were all markedly decreased by LY294002, accompanied by suppressed pulmonary expression of HMGB1. At the same time, we observed elevated protein levels of cleaved caspase-1 and IL-1 beta after TDI challenge, as well as increased immunoreactivity in lung, all of which were significantly recovered by LY294002. While both the protein expression and immunodistribution of NLRP3 in the lung stayed unchanged.These data suggest that PI3K mediates lung caspase-1 activation and HMGB1 production in TDI-induced murine asthma model. (C) 2015 Elsevier Ireland Ltd. All rights reserved.