Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
BMC Pulm Med. 2022 Feb 11;22(1):61. doi: 10.1186/s12890-022-01832-3.
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.
甲苯二异氰酸酯（TDI）暴露是哮喘的一个重要致病因素。我们之前报道过，晚期糖基化终产物受体（RAGE）在 TDI 诱导的哮喘中发挥关键作用。组蛋白去乙酰化酶（HDAC）已被报道在哮喘发病机制中很重要。然而，其对 TDI 诱导的哮喘的影响尚不清楚。本研究旨在通过 TDI 诱导的小鼠哮喘模型，确定 RAGE 和 HDAC 在调节气道炎症中的作用。
用 TDI 致敏和激发 BALB/c 小鼠建立哮喘模型。在每次激发前，腹腔内给予 FPS-ZM1（RAGE 抑制剂）、JNJ-26482585 和罗米地辛（HDAC 抑制剂）。在体外，用 TDI-人血清白蛋白（TDI-HSA）刺激人支气管上皮细胞系 16HBE。构建和评估 RAGE 敲低细胞，并在实验中也使用 MK2006（AKT 抑制剂）。
在 TDI 诱导的哮喘小鼠中，RAGE、HDAC1 和 p-AKT/t-AKT 的表达上调，而 FPS-ZM1 可减弱这些表达。TDI 诱导的哮喘小鼠气道反应性、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均显著增加。这些增加被 JNJ-26482585 和罗米地辛抑制。此外，JNJ-26482585 和罗米地辛改善了 TDI 诱导的哮喘中 E-钙粘蛋白和β-连环蛋白的重新分布。在 TDI-HSA 刺激的 16HBE 细胞中，RAGE 敲低减弱了 HDAC1 和磷酸化 AKT（p-AKT）的上调。用 AKT 抑制剂 MK2006 处理可抑制 TDI 诱导的 HDAC1 表达。
这些发现表明，RAGE 通过 PI3K/AKT 通路调节 HDAC1 的表达，抑制 HDAC 可防止 TDI 诱导的气道炎症。
