RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model.
RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model.
复制标题
在甲苯二异氰酸酯诱导的小鼠哮喘模型中，RAGE 通过 HDAC1 通路介导气道炎症
DOI：
10.1186/s12890-022-01832-3
复制
发表时间：
2022-02-11
影响因子：
3.1
通讯作者：
Zhao H
中科院分区：
文献类型：
--
作者：
Peng X;Huang M;Zhao W;Lan Z;Wang X;Yuan Y;Li B;Yu C;Liu L;Dong H;Cai S;Zhao H
接触甲苯二异氰酸酯(TDI)是哮喘的一个重要致病因素。我们之前曾报道，晚期糖基化终产物受体(RAGE)在TDI诱导的哮喘中起关键作用。组蛋白脱乙酰酶(HDAC)在哮喘发病机制中起重要作用。然而，它对TDI诱导的哮喘的影响尚不清楚。本研究的目的是利用TDI诱导的小鼠哮喘模型，确定RAGE和HDAC在调节呼吸道炎症中的作用。用TDI致敏和激发BALB/c小鼠建立哮喘模型。每次激发前分别给予FPS-ZM1(RAGE抑制剂)、JNJ-26482585和罗米地平(HDAC抑制剂)。体外，用TDI-人血清白蛋白(TDI-HSA)刺激人支气管上皮细胞系16HBE。构建和评价了RAGE基因敲除细胞，并在实验中使用了MK2006(AKT抑制剂)。在TDI诱导的哮喘小鼠，RAGE、HDAC1和p-AKT/t-AKT的表达上调，这些表达被FPS-ZM1减弱。TDI诱导的哮喘小鼠的气道反应性、淋巴上清液中Th2细胞因子水平、IgE、气道炎症和杯状细胞化生显著增加。这些增加被JNJ-26482585和罗米地辛抑制。此外，JNJ-26482585和罗米地辛均能改善哮喘患者E-钙粘附素和β-连环素的再分布。在TDI-HSA刺激的16HBE细胞中，RAGE的下调减弱了HDAC1和磷酸化AKT(p-AKT)的上调。AKT抑制剂MK2006可抑制TDI诱导的HDAC1表达。这些发现表明，RAGE通过PI3K/AKT途径调节HDAC1的表达，抑制HDAC可防止TDI诱导的呼吸道炎症。网上版载有补充材料，可在10.1186/s12890-022-01832-3查阅。
Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model. BALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments. In TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and β-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression. These findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation. The online version contains supplementary material available at 10.1186/s12890-022-01832-3.
登录
查看更多内容
影响因子：
--
作者：
Sundar IK;Javed F;Romanos GE;Rahman I
通讯作者：
Rahman I
影响因子：
5.6
作者：
Thakur V;Alcoreza N;Cazares J;Chattopadhyay M
通讯作者：
Chattopadhyay M
影响因子：
5.8
作者：
Oczypok EA;Perkins TN;Oury TD
通讯作者：
Oury TD
DOI：
10.1164/rccm.2110060
发表时间：
2002-08-01
影响因子：
24.7
作者：
Ito, K;Caramori, G;Adcock, IM
通讯作者：
Adcock, IM
影响因子：
3.7
作者：
Desjardins D;Liu Y;Crosson CE;Ablonczy Z
通讯作者：
Ablonczy Z