鸢尾黄素调节花生四烯酸代谢改善RSV诱导哮喘小鼠气道炎症的机制研究

Mechanism of Tectorigenin Regulating Arachidonic Acid Metabolism and Improving Airway Inflammation in RSV-Induced Asthmatic Mice

    摘要
  • 摘要:
    目的 研究鸢尾黄素对呼吸道合胞病毒（RSV）诱导哮喘小鼠的治疗作用，并结合代谢组学探讨其作用机制。
    方法 将BALB/c 小鼠随机分为对照组，模型组，鸢尾黄素低、高剂量组（10、20 mg·kg-1），地塞米松组。使用RSV联合屋尘螨（HDM）构建哮喘模型，给药后HE染色观察肺组织病理学变化；PAS染色评估气道黏液分泌情况；ELISA检测血清中白介素-4（IL-4）、白介素-5（IL-5）、白介素-13（IL-13）、白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、5-脂氧合酶（5-LOX）和半胱氨酰白三烯（CysLTs）的含量；GC-MS技术研究RSV诱导哮喘小鼠肺组织的代谢组学变化。Western blot检测肺组织中花生四烯酸-5-脂加氧酶（ALOX5）的蛋白表达。
    结果 与模型组相比，鸢尾黄素低、高剂量可减轻肺组织病理损伤（P<0.05，P<0.01），减少气道黏液分泌（P<0.05，P<0.01）；降低血清中IL-4、IL-5、IL-13、IL-1β、TNF-α的含量（P<0.05，P<0.01）。代谢组学结果显示，鸢尾黄素高剂量治疗可改善小鼠肺组织中白细胞三烯A4（LTA4）、白细胞三烯B4（LTB4）、白细胞三烯D4（LTD4）、白细胞三烯E4（LTE4）、花生四烯酸（AA）、5-羟基二十四烯酸（5-HETE）等代谢紊乱。差异代谢物主要富集于花生四烯酸代谢等通路。与模型组相比，鸢尾黄素高剂量可降低小鼠血清中5-LOX、CysLTs的含量（P<0.05），抑制肺组织中ALOX5蛋白表达（P<0.05）。
    结论 鸢尾黄素可能通过调节花生四烯酸代谢改善RSV诱导的哮喘，其机制与降低5-LOX、ALOX5的表达，抑制AA向CysLTs转化，减轻气道炎症有关。

     

    Abstract:
    OBJECTIVE To investigate the therapeutic effect of tectorigenin on respiratory syncytial virus (RSV)-induced asthma, and to explore its mechanism by metabolomics.
    METHODS BALB/C mice were randomly divided into normal group, model group, tectorigenin low and high dose groups (10, 20 mg·kg-1) and positive drug dexamethasone group. RSV-induced asthma model was established by RSV combined with house dust mite (HDM). Lung histopathology was observed by HE staining and airway mucus secretion was observed by PAS staining. Serum levels of Interleukin-4 (IL-4), Interleukin-5 (IL-5), Interleukin-13 (IL-13), Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), 5-Lipoxygenase (5-LOX) and Cysteinyl leukotrienes (CysLTs) were measured by ELISA. Metabolomic changes of lung tissue in RSV-induced asthmatic mice were examined by GC-MS. The protein expression of ALOX5 in lung tissue was detected by Western blot.
    RESULTS Compared with the model group, the pathological injury of lung tissue and mucus secretion of airway were reduced in low and high dose groups of tectorigenin (P<0.05,P<0.01). The levels of IL-4, IL-5, IL-13, IL-1β, TNF-α in serum were decreased in low and high dose groups of tectorigenin (P<0.05,P<0.01). The results of metabolomics showed that high-dose tectorigenin treatment could improve the metabolic disorders of leukotriene A4 (LTA4) , leukotriene B4 (LTB4), leukotriene D4 (LTD4), leukotriene E4 (LTE4), arachidonic acid (AA) and 5-hydroxytetradecenoic acid (5-HETE) in the lung tissue of the model group. The differential metabolites were mainly enriched in pathways such as arachidonic acid metabolism. Compared with the model group, the levels of 5-LOX and CysLTs in serum and the protein expression of ALOX5 in the lung tissue of high-dose tectorigenin group were decreased (P<0.05).
    CONCLUSION Tectorigenin might improve RSV-induced asthma by regulating arachidonic acid metabolism. The mechanism was related to reducing the expression of 5-LOX and ALOX5, inhibiting the transformation of arachidonic acid to CysLTs and reducing airway inflammation.

     

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