β-谷甾醇靶向糖皮质激素受体减少过敏性哮喘气道炎症和重塑

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Jianfeng Xu , Lei Yang , Tiantian Lin
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引用次数: 4

摘要

引言大多数哮喘患者的症状可以通过糖皮质激素治疗来控制,但长期或高剂量使用会产生不良反应。因此,寻找新的治疗策略至关重要。β-谷甾醇可抑制卵清蛋白(OVA)诱导的小鼠Ⅱ型炎症,但其作用机制尚不清楚。方法通过分子对接分析β-谷甾醇与糖皮质激素受体(GR)的结合活性。用不同浓度(0、1、5、10、20和50μg/mL)的β-谷甾醇处理人支气管上皮细胞(BEAS-2B)和人支气管平滑肌细胞(HBSMC)以选择合适的浓度。在转化生长因子(TGF)-β1处理的BEAS-2B和HBSMC中,用20μg/mLβ-谷甾醇或地塞米松(Dex)处理细胞,以分析其可能的机制。在OVA诱导的小鼠中,给予2.5mg/kgβ-谷甾醇或Dex以分析β-谷固醇的治疗机制。使用GR拮抗剂RU486来证实β-谷甾醇治疗哮喘的机制。结果在BEAS-2B和HBSMC中发现β-谷甾醇与GR有良好的结合(评分为−8.2kcal/mol),并且GR的表达随着β-谷固醇剂量的增加而上调。在TGF-β1诱导的BEAS-2B中,β-谷甾醇显著降低了白细胞介素(IL)-25和IL-33的分泌,在TGF-α1诱导的HBSMC中,1A胶原和α-平滑肌肌动蛋白(SMA)的水平降低。在OVA攻击小鼠中,β-谷甾醇治疗通过抑制Ⅱ型免疫反应和胶原沉积来改善气道炎症和重塑。β-谷甾醇在体外和体内的治疗效果与地塞米松相似。RU486治疗明显阻碍了β-谷甾醇在TGF-β1诱导的细胞和OVA诱导的小鼠中的治疗作用。结论β-谷甾醇结合GR在哮喘治疗中发挥作用。β-谷甾醇是一种潜在的治疗过敏性哮喘的药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
β-sitosterol targets glucocorticoid receptor to reduce airway inflammation and remodeling in allergic asthma

Introduction

In most asthma patients, symptoms are controlled by treatment with glucocorticoid, but long-term or high-dose use can produce adverse effects. Therefore, it is crucial to find new therapeutic strategies. β-sitosterol could suppress type Ⅱ inflammation in ovalbumin (OVA)-induced mice, but its mechanisms have remained unclear.

Methods

A binding activity of β-sitosterol with glucocorticoid receptor (GR) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) and human bronchial smooth muscle cells (HBSMC) were treated with different concentrations (0, 1, 5, 10, 20, and 50 μg/mL) of β-sitosterol for suitable concentration selection. In transforming growth factor (TGF)-β1 treated BEAS-2B and HBSMC, cells were treated with 20 μg/mL β-sitosterol or dexamethasone (Dex) to analyze its possible mechanism. In OVA-induced mice, 2.5 mg/kg β-sitosterol or Dex administration was performed to analyze the therapeutic mechanism of β-sitosterol. A GR antagonist RU486 was used to confirm the mechanism of β-sitosterol in the treatment of asthma.

Results

A good binding of β-sitosterol to GR (score = −8.2 kcal/mol) was found, and the GR expression was upregulated with β-sitosterol dose increase in BEAS-2B and HBSMC. Interleukin (IL)-25 and IL-33 secretion was significantly decreased by β-sitosterol in the TGF-β1-induced BEAS-2B, and the levels of collagen 1A and α-smooth muscle actin (SMA) were reduced in the TGF-β1-induced HBSMC. In the OVA-challenged mice, β-sitosterol treatment improved airway inflammation and remodeling through suppressing type Ⅱ immune response and collagen deposition. The therapeutic effects of β-sitosterol were similar to Dex treatment in vitro and in vivo. RU486 treatment clearly hampered the therapeutic effects of β-sitosterol in the TGF-β1-induced cells and OVA-induced mice.

Conclusion

This study identified that β-sitosterol binds GR to perform its functions in asthma treatment. β-sitosterol represent a potential therapeutic drug for allergic asthma.

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来源期刊
CiteScore
6.20
自引率
0.00%
发文量
41
审稿时长
42 days
期刊介绍: Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.
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