Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, People's Republic of China.
Pharmacol Rep. 2020 Aug;72(4):1011-1020. doi: 10.1007/s43440-019-00027-8. Epub 2020 Jan 8.
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.
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 CD4T 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 CD4T cell subsets was evaluated with real-time PCR. Cytokine levels in bronchoalveolar lavage fluid (BALF) and serum was determined with ELISA.
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.
Acetyl-CoA carboxylase inhibitor TOFA might have a distinct effect on asthmatic airway inflammation and airway hyperresponsiveness.
乙酰辅酶 A 羧化酶（ACC）调节 Th1、Th2、Th17 细胞和 Treg 细胞的分化，这些细胞在哮喘的气道炎症中起着关键作用。本研究旨在探讨 ACC 在哮喘发病机制中的作用。
鸡卵清白蛋白致敏和攻击的小鼠分为三组，PBS 组、DMSO（TOFA 溶剂）组和 ACC 抑制剂 5-十四烷氧基-2-糠酸（TOFA）+DMSO 组。采用组织学评估气道炎症，流式细胞术评估肺和脾中 CD4T 细胞亚群的百分比，FinePointe RC 系统评估气道反应性。采用实时 PCR 评估 CD4T 细胞亚群特征性转录因子的表达。采用 ELISA 测定支气管肺泡灌洗液（BALF）和血清中的细胞因子水平。
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 的表达没有显著影响。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 显著降低肺和脾中 Th1、Th2、Th17 细胞的百分比、肺中 GATA3 和 RORγt 的表达以及 BALF 和血清中 IFN-γ、IL-4、IL-17A 的水平。TOFA 对 Treg 细胞的百分比、IL-10 水平以及 T-bet 和 Foxp3 的表达无显著影响。
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具有显著作用。
