PI3K/AKT/mTOR and TLR4/MyD88/NF-κB Signaling Inhibitors Attenuate Pathological Mechanisms of Allergic Asthma
PI3K/AKT/mTOR and TLR4/MyD88/NF-κB Signaling Inhibitors Attenuate Pathological Mechanisms of Allergic Asthma
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PI 3 K/AKT/mTOR和TLR 4/MyD 88/NF-κB信号通路抑制剂减轻过敏性哮喘的病理机制
DOI：
10.1007/s10753-021-01466-3
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发表时间：
2021-04-16
期刊：
影响因子：
5.1
通讯作者：
Zhao, Limin
中科院分区：
文献类型：
--
作者：
Ma, Baowei;Athari, Seyyed Shamsadin;Zhao, Limin
哮喘是一种炎症性呼吸道疾病，哮喘发作时的主要问题是支气管收缩、呼吸道炎症和呼吸道阻塞。目前认为Th1/Th2和Th17/Treg失衡是哮喘发病的重要因素。用mTOR、PI3K、Akt和MyD88等信号分子操纵这些分子可以控制哮喘。建立小鼠过敏性哮喘模型，分别用氯胺酮、二甲双胍、二甲双胍、氯胺酮、三氯硝胺、LY294002和Torin2进行治疗。测定MCH激发试验、BALF‘s Eos计数、IL-4、IL-5、干扰素-γ、二十烷类化合物、总IgE水平。检测MUC5a、Foxp3、RoR-Gamma t、PI3K、mTOR、Akt、PU.1、MyD88基因表达，并进行组织病理学研究。所有6种成分均能降低哮喘组的Penh值、总IgE、IL-4和IL-5水平，降低MUC5a、ROR-γt、MyD88和mTOR的表达，降低杯状细胞增生和粘液高分泌。二甲双胍、氯胺酮、甘草次碱、LY294002和Torin2可降低嗜酸性粒细胞百分率和Cys-LT水平。Triciriine、LY294002和Torin2的干扰素-γ水平升高。二甲双胍、二甲双胍和氯胺酮、三氯核苷、LY294002和Torin2减少Akt和PI3K的表达，减少支气管和血管周围的炎症，并增加Foxp3的表达。Torin2对PU1的表达有影响。通过靶向分子抑制PI3K/AKT/mTOR和TLR4/MyD88/NF-kappaB信号通路可以减轻哮喘的病理改变，在气道保护中发挥重要作用。
Asthma is an inflammatory airway disease wherein bronchoconstriction, airway inflammation, and airway obstruction during asthma attacks are the main problems. It is recognized that imbalance of Th1/Th2 and Th17/Treg is a critical factor in asthma pathogenesis. Manipulation of these with signaling molecules such as mTOR, PI3K, Akt, and MyD88 can control asthma. Mouse model of allergic asthma was produced and treated with ketamine, metformin, metformin and ketamine, triciribine, LY294002, and torin2. MCh challenge test, BALf's Eos Count, the IL-4, 5, INF-gamma, eicosanoid, total IgE levels were determined. The MUC5a, Foxp3, ROR gamma t, PI3K, mTOR, Akt, PU.1, and MyD88 gene expressions and histopathology study were done. Asthma groups that were treated with all six components had reduced Penh value, total IgE, IL-4 and IL-5 levels, MUC5a, ROR gamma t, MyD88 and mTOR expression, goblet cell hyperplasia, and mucus hyper-secretion. The eosinophil percentage and Cys-LT level were decreased by metformin and ketamine, triciribine, LY294002, and torin2. The level of IFN-gamma was increased in triciribine, LY294002, and torin2. Metformin, metformin and ketamine, triciribine, LY294002, and torin2 reduced Akt and PI3K expression, peribronchial and perivascular inflammation, and increased expression of Foxp3. Torin2 had an effect on PU.1 expression. Inhibition of PI3K/AKT/mTOR and TLR4/MyD88/NF-kappa B signaling with targeted molecules can attenuate asthma pathology and play an important role in airways protection.