Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
Department of Pharmaceutical Chemistry, International Medical University, Kuala Lumpur, Malaysia.
Pulm Pharmacol Ther. 2018 Dec;53:39-51. doi: 10.1016/j.pupt.2018.09.008. Epub 2018 Sep 21.
Toluene diisocyanate (TDI) is a major cause of chemical-induced occupational asthma, which contributes about 15% of global asthma burden. Resistance and compounded side effects associated with the use of corticosteroid in asthma necessitate the search for alternative drugs. Andrographolide (AGP), a naturally occurring diterpene lactone is known to exhibit various bioactivities. Its ability to ameliorate cardinal features of allergic asthma was previously suggested in an eosinophilic asthma endotype. However, its potential antiasthma activity and mechanism of action in a neutrophilic occupational asthma model, as well as its effect on epithelial dysfunction remain unknown. BALB/c mice were dermally sensitised with 0.3% TDI or acetone olive oil (AOO) vehicle on day 1 and 8, followed by 0.1% TDI intranasal challenge on days 15, 18 and 21. Endpoints were evaluated via bronchoalveolar lavage fluid (BALF) cell analysis, 2',7'-dichlorofluorescein diacetate (DCFDA) assays, immunoblotting, immunohistochemistry and methacholine challenge test. Decreases in total and differential leukocyte counts of BALF were recorded in AGP-treated animals. The compound dose-dependently reduced intracellular de-esterification of DCFDA, thus suggesting AGP's potential to inhibit intracellular reactive oxygen species (ROS). Mechanistically, the treatment prevented TDI-induced aberrant E-cadherin distribution and restored airway epithelial β-catenin at cell to cell contact site. Furthermore, AGP ameliorated TDI induced pulmonary collagen deposition. In addition, the treatment significantly upregulated pulmonary HO-1, Nrf2 and phospho-p38 levels. Airway hyperresponsiveness was markedly suppressed among AGP-treated animals. Collectively, these findings suggest AGP's protective function against TDI-induced airway epithelial barrier dysfunction and oxidative lung damage possibly through the upregulation of adherence junction proteins and the activation of p38/Nrf2 signalling. This study elucidates the therapeutic potential of AGP in the control and management of chemical-induced allergic asthma. To the best of our knowledge, the potential anti-asthma activity of AGP in TDI-induced occupational asthma has not been reported previously.
甲苯二异氰酸酯（TDI）是化学诱导职业性哮喘的主要原因，占全球哮喘负担的 15%左右。哮喘患者使用皮质类固醇的耐药性和复合副作用需要寻找替代药物。穿心莲内酯（AGP）是一种天然存在的二萜内酯，已知具有多种生物活性。以前在嗜酸性粒细胞哮喘表型中已经提出，它具有改善过敏性哮喘的主要特征的能力。然而，它在中性粒细胞职业性哮喘模型中的潜在抗哮喘活性及其作用机制，以及它对上皮功能障碍的影响仍不清楚。BALB/c 小鼠在第 1 天和第 8 天用 0.3%TDI 或丙酮橄榄油（AOO）载体进行皮肤致敏，然后在第 15、18 和 21 天进行 0.1%TDI 鼻腔内挑战。通过支气管肺泡灌洗液（BALF）细胞分析、2'，7'-二氯荧光素二乙酸酯（DCFDA）测定、免疫印迹、免疫组织化学和乙酰甲胆碱挑战试验评估终点。在 AGP 处理的动物中，BALF 中的总白细胞和白细胞分类计数减少。该化合物剂量依赖性地降低了 DCFDA 的细胞内去酯化，从而表明 AGP 具有抑制细胞内活性氧（ROS）的潜力。从机制上讲，该治疗方法防止了 TDI 引起的 E-钙粘蛋白分布异常，并恢复了气道上皮细胞间β-连环蛋白的细胞接触部位。此外，AGP 改善了 TDI 诱导的肺胶原沉积。此外，该治疗方法显著上调了肺 HO-1、Nrf2 和磷酸化 p38 水平。气道高反应性在 AGP 处理的动物中明显受到抑制。总之，这些发现表明 AGP 具有防止 TDI 诱导的气道上皮屏障功能障碍和氧化肺损伤的保护功能，可能是通过上调粘附连接蛋白和激活 p38/Nrf2 信号通路。这项研究阐明了 AGP 在控制和管理化学诱导的过敏性哮喘中的治疗潜力。据我们所知，AGP 在 TDI 诱导的职业性哮喘中的潜在抗哮喘活性以前尚未报道过。
