Xu Ronghua, Deng Huiming, Gan Lianfang, Zhong Lifan, Deng Yanxi, Wang Qianru, Lv Chuanzhu, Huang Ling
Hainan Province Key Laboratory for Drug Preclinical Study of Pharmacology and Toxicology Research, Hainan Medical University, Haikou, China.
Department of Gastrointestinal Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China.
Ann Transl Med. 2022 Feb;10(4):225. doi: 10.21037/atm-22-386.
Aminophylline is widely used for the treatment of asthma, but the therapeutic dose is very close to the toxic dose, which makes this drug prone to accumulation poisoning. In the present study, we explored whether the Chinese herbal component, Praeruptorin E (PE), enhances anti-asthma efficacy and prevents the toxicity of aminophylline.
First, an ovalbumin (OVA)-induced mouse model of asthma, immunohistochemistry, pathological staining, and bronchoalveolar lavage fluid (BALF) were used to detect the lung condition of asthmatic mice. The content of Th2 cytokines in serum was measured by enzyme-linked immunosorbent assay (ELISA), and the expression of related proteins was detected by Western blotting and immunofluorescence. Concentrations of theophylline and its metabolites in rat serum were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). siRNA transfection and chromatin immunoprecipitation (ChIP) were used to investigate the mechanism of PE.
PE was found to synergize with aminophylline to reduce the infiltration of inflammatory cells, collagen deposition, and mucus hyperplasia in the lungs of asthmatic mice. It inhibited the expression of Th2 cytokines, interleukin (IL)-4, IL-5, and IL-13; promoted lung tissue repair; and reduced the toxic effect of aminophylline on the heart. Moreover, LC-MS/MS analysis showed that PE reduced the plasma concentration of the parent theophylline and its metabolite 1,3-dimethyluric acid (1,3-DMU). PE facilitated aminophylline's suppression of nuclear factor-κB (), and increased the expression of the xenobiotic nuclear receptor pregnane X receptor () and its primary target gene, [this is the mouse homolog of cytochrome P450 3A ()] in the asthmatic mouse liver and in the L-02 human fetal hepatocyte cell culture model. In addition, the ChIP assay revealed that PE attenuated the binding of to the promoter region of the PXR gene and prevented the suppression of gene expression by .
PE has a dual function in enhancing the immune regulation and anti-inflammatory effects of theophylline, as well as preventing theophylline toxicity by targeting the NF-κB/PXR/CYP3A4 axis. PE is a promising herbal medicine that will benefit asthmatics taking theophylline.
氨茶碱被广泛用于治疗哮喘，但其治疗剂量与中毒剂量非常接近，这使得该药物容易发生蓄积中毒。在本研究中，我们探讨了中药成分白花前胡素E（PE）是否能增强抗哮喘疗效并预防氨茶碱的毒性。
首先，利用卵清蛋白（OVA）诱导的小鼠哮喘模型、免疫组化、病理染色及支气管肺泡灌洗液（BALF）检测哮喘小鼠的肺部状况。采用酶联免疫吸附测定（ELISA）法检测血清中Th2细胞因子的含量，通过蛋白质印迹法和免疫荧光法检测相关蛋白的表达。采用液相色谱-串联质谱（LC-MS/MS）法分析大鼠血清中茶碱及其代谢产物的浓度。运用小干扰RNA（siRNA）转染和染色质免疫沉淀（ChIP）技术研究PE的作用机制。
发现PE与氨茶碱协同作用，可减少哮喘小鼠肺部炎症细胞浸润、胶原沉积和黏液增生。它抑制Th2细胞因子白细胞介素（IL）-4、IL-5和IL-13的表达；促进肺组织修复；并降低氨茶碱对心脏的毒性作用。此外，LC-MS/MS分析表明，PE降低了母体茶碱及其代谢产物1,3-二甲基尿酸（1,3-DMU）的血浆浓度。PE促进氨茶碱对核因子κB（）的抑制作用，并增加哮喘小鼠肝脏和L-02人胎儿肝细胞培养模型中外源性核受体孕烷X受体（）及其主要靶基因[这是细胞色素P450 3A（）的小鼠同源物]的表达。此外，ChIP分析显示，PE减弱了与PXR基因启动子区域的结合，并防止对基因表达的抑制。
PE在增强茶碱的免疫调节和抗炎作用以及通过靶向NF-κB/PXR/CYP3A4轴预防茶碱毒性方面具有双重功能。PE是一种有前景的草药，将使服用茶碱的哮喘患者受益。
