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Different effects of acetyl-CoA carboxylase inhibitor TOFA on airway inflammation and airway resistance in a mice model of asthma

乙酰辅酶a 羧化酶抑制剂 TOFA 对哮喘小鼠气道炎症和气道阻力的不同作用

  • 影响因子:2.93
  • DOI:10.1007/s43440-019-00027-8
  • 作者列表:"Zhu, Fang-fang","Wang, Yi-min","He, Guang-zhen","Chen, Yi-fei","Gao, Ya-dong
  • 发表时间:2020-01-08
Abstract

Background and objective Acetyl CoA carboxylase (ACC) regulates the differentiation of Th1, Th2, Th17 cells and Treg cells, which play a critical role in airway inflammation of asthma. Here we investigated the role of ACC in the pathogenesis of asthma. Methods Chicken Ovalbumin-sensitized and -challenged mice were divided into three groups, PBS group, DMSO (solvent of TOFA) group and ACC inhibitor 5-tetradecyloxy-2-furoic acid (TOFA) + DMSO group. Airway inflammation was assessed with histology, percentages of CD4^+T cell subsets in lung and spleen was assessed with flow cytometry, and airway responsiveness was assessed with FinePointe RC system. The expression of characteristic transcription factors of CD4^+T cell subsets was evaluated with real-time PCR. Cytokine levels in bronchoalveolar lavage fluid (BALF) and serum was determined with ELISA. Results In asthma mice, the expression of ACC increased, while the expression of phosphorylated ACC (pACC) decreased. TOFA had no significant effect on pACC expression. TOFA reduced serum IgE, airway inflammatory cells infiltration and goblet cell hyperplasia, but dramatically increased airway responsiveness. TOFA significantly reduced the percentages of Th1, Th2, Th17 cells in lung and spleen, the expression of GATA3 and RORγt in lung, and IFN-γ, IL-4, IL-17A levels in BALF and serum. TOFA had no significant effect on the percentage of Treg cells, IL-10 level and the expression of T-bet and Foxp3. Conclusion Acetyl-CoA carboxylase inhibitor TOFA might have a distinct effect on asthmatic airway inflammation and airway hyperresponsiveness.

摘要

背景与目的乙酰辅酶a 羧化酶 (ACC) 调节 Th1 、 Th2 、 Th17 细胞和 Treg 细胞的分化,在哮喘气道炎症中发挥关键作用。在这里,我们调查了 ACC 在哮喘发病机制中的作用。方法鸡卵清蛋白致敏和激发小鼠分为 3 组,PBS 组、 DMSO (TOFA 溶剂) 组和 ACC 抑制剂 5-十四氧基-2-糠酸 (TOFA) + DMSO 组。用组织学评估气道炎症,用流式细胞术评估肺和脾脏中 CD4 ^ + T 细胞亚群的百分比,用 FinePointe RC 系统评估气道反应性。用 real-time PCR 评价 CD4 ^ + T 细胞亚群特征性转录因子的表达。用 ELISA 法测定支气管肺泡灌洗液 (BALF) 和血清中细胞因子水平。结果在哮喘小鼠中,ACC 的表达增加,而磷酸化 ACC (pACC) 的表达减少。TOFA 对 pACC 表达无显著影响。TOFA 降低血清 IgE 、气道炎症细胞浸润和杯状细胞增生,但显著增加气道反应性。TOFA 显著降低肺和脾脏中 Th1 、 Th2 、 Th17 细胞百分比,肺 GATA3 和 ror γ t 表达,BALF 和血清中 IFN-γ 、 IL-4 、 IL-17A 水平。TOFA 对 Treg 细胞百分比、 IL-10 程度和 T-bet 、 foxp3 表达无显著影响。结论乙酰辅酶a 羧化酶抑制剂 TOFA 可能对哮喘气道炎症和气道高反应性有明显的影响。

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