Lee H, Han A R, Kim Y, Choi S H, Ko E, Lee N Y, Jeong J H, Kim S H, Bae H
Department of Physiology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):591-603. doi: 10.1177/039463200902200305.
Clinical and experimental studies have established eosinophilia as a sign of allergic disorders. Activation of eosinophils in the airways is believed to cause epithelial tissue injury, contraction of airway smooth muscle and increased bronchial responsiveness. As part of the search for new antiasthmatic agents produced by medicinal plants, the effects of 270 standardized medicinal plant extracts on cytokine-activated A549 human lung epithelial cells were evaluated. After several rounds of activity-guided screening, the new natural compound, 1H,8H-Pyrano[3,4-c]pyran-1,8-dione (PPY), was isolated from Vitex rotundifolia L. To elucidate the mechanism by which the anti-asthmatic responses of PPY occurred in vitro, lung epithelial cells (A549 cell) were stimulated with TNF-alpha, IL-4 and IL-1beta to induce the expression of chemokines and adhesion molecules involved in eosinophil chemotaxis. PPY treatments reduced the expression of eotaxin, IL-8, IL-16 and VCAM-1 mRNA significantly. Additionally, PPY reduced eotaxin secretion in a dose-dependent manner and significantly inhibited eosinophil migration toward A549 medium. In addition, PPY treatment suppressed the phosphorylation of p65 and ERK1/2, suggesting that it can inhibit the MAPK/NF-KB pathway. To clarify the anti-inflammatory and antiasthmatic effects of PPY in vivo, we examined the influence of PPY on the development of pulmonary eosinophilic inflammation in a murine model of asthma. To accomplish this, mice were sensitized and challenged with ovalbumin (OVA) and then examined for the following typical asthmatic reactions: an increase in the number of eosinophils in BALF; the presence of Th2 cytokines such as IL-4 and IL-5 in the BALF; the presence of allergen-specific IgE in the serum; and a marked influx of inflammatory cells into the lung. Taken together, our results revealed that PPY exerts profound inhibitory effects on the accumulation of eosinophils into the airways while reducing the levels of IL-4, IL-5, and IL-13 in the BALF. Therefore, these results suggest that PPY may be useful as a new therapeutic drug for the treatment of allergic asthma.
临床和实验研究已证实嗜酸性粒细胞增多是过敏性疾病的一个标志。气道中的嗜酸性粒细胞激活被认为会导致上皮组织损伤、气道平滑肌收缩以及支气管反应性增加。作为寻找药用植物产生的新型抗哮喘药物的一部分，评估了270种标准化药用植物提取物对细胞因子激活的A549人肺上皮细胞的影响。经过几轮活性导向筛选，从蔓荆子中分离出新型天然化合物1H,8H-吡喃并[3,4-c]吡喃-1,8-二酮（PPY）。为阐明PPY在体外产生抗哮喘反应的机制，用肿瘤坏死因子-α、白细胞介素-4和白细胞介素-1β刺激肺上皮细胞（A549细胞），以诱导参与嗜酸性粒细胞趋化作用的趋化因子和黏附分子的表达。PPY处理显著降低了嗜酸性粒细胞趋化因子、白细胞介素-8、白细胞介素-16和血管细胞黏附分子-1 mRNA的表达。此外，PPY以剂量依赖方式减少嗜酸性粒细胞趋化因子的分泌，并显著抑制嗜酸性粒细胞向A549培养基的迁移。此外，PPY处理抑制了p65和ERK1/2的磷酸化，表明它可以抑制丝裂原活化蛋白激酶/核因子-κB途径。为阐明PPY在体内的抗炎和抗哮喘作用，我们在哮喘小鼠模型中研究了PPY对肺部嗜酸性炎症发展的影响。为此，用卵清蛋白（OVA）对小鼠进行致敏和激发，然后检测以下典型的哮喘反应：支气管肺泡灌洗液（BALF）中嗜酸性粒细胞数量增加；BALF中白细胞介素-4和白细胞介素-5等Th2细胞因子的存在；血清中过敏原特异性IgE的存在；以及炎症细胞大量涌入肺部。综上所述，我们的结果表明PPY对嗜酸性粒细胞在气道中的积聚具有显著的抑制作用，同时降低了BALF中白细胞介素-4、白细胞介素-5和白细胞介素-13的水平。因此，这些结果表明PPY可能作为治疗过敏性哮喘的新型治疗药物有用。
