Department of Physiology, College of Korean Medicine, Kyung Hee University, #1 Hoeki-Dong, Dongdaemoon-gu, Seoul 130-701, Republic of Korea.
Bioorg Med Chem. 2013 Nov 1;21(21):6359-65. doi: 10.1016/j.bmc.2013.08.045. Epub 2013 Sep 3.
Eosinophilia is one of the characteristic signs of allergic inflammation. Massive migration of eosinophils to the airways can cause epithelial tissue injury, contraction of airway smooth muscle and increased bronchial responsiveness. Previously, we discovered a new compound, 1H,8H-pyrano[3,4-c]pyran-1,8-dione (PPY), derived from the fruit of Vitex rotundifolia L. and evaluated its anti-inflammatory and anti-asthmatic properties. In this study, we synthesized a new modified compound, 4-acetyl-3-methyl-6-(3,4,5-trimethoxyphenyl) pyrano[3,4-c]pyran-1,8-dione (PPY-345), which was based on the PPY skeleton, and we evaluated its anti-asthmatic effects. To evaluate the anti-asthmatic effect of PPY-345 in vitro, A549 lung epithelial cells were stimulated with TNF-alpha, IL-4 and IL-1-beta to induce the expression of CCL11 (Eotaxin), a chemokine involved in eosinophil chemotaxis. To characterize the anti-asthmatic properties of PPY-345 in vivo, we examined the influence of PPY-345 in an ovalbumin (OVA)-induced asthma model. PPY-345 treatments significantly reduced CCL11 secretion. PPY-345 treatment did not inhibit the translocation of NF-κB into the nucleus but suppressed the phosphorylation of signal transducers and activators of transcription 6 (STAT6). PPY-345 treatment significantly reduced airway hyperreactivity as measured by whole-body plethysmography. PPY-345 further reduced total cells, including eosinophil, macrophage and lymphocytes, in the BAL fluid, goblet cell hyperplasia and myosin light chain 2 positive smooth muscle cell area in the lung tissue. Additionally, PPY-345 significantly suppressed the levels of OVA-IgE present in the serum. These results suggested that PPY-345 could improve asthma symptoms in OVA-sensitized mice.
嗜酸性粒细胞增多是过敏炎症的特征之一。大量嗜酸性粒细胞迁移到气道会导致上皮组织损伤、气道平滑肌收缩和支气管反应性增加。此前，我们发现了一种来自三叶木通果实的新化合物 1H，8H-吡喃并[3，4-c]吡喃-1，8-二酮（PPY），并评估了其抗炎和抗哮喘特性。在这项研究中，我们基于 PPY 骨架合成了一种新的修饰化合物 4-乙酰基-3-甲基-6-（3,4,5-三甲氧基苯基）吡喃并[3,4-c]吡喃-1,8-二酮（PPY-345），并评估了其抗哮喘作用。为了评估 PPY-345 在体外的抗哮喘作用，我们用 TNF-α、IL-4 和 IL-1-β刺激 A549 肺上皮细胞，诱导趋化因子 CCL11（Eotaxin）的表达，该趋化因子参与嗜酸性粒细胞趋化。为了表征 PPY-345 在体内的抗哮喘特性，我们在卵清蛋白（OVA）诱导的哮喘模型中检查了 PPY-345 的影响。PPY-345 治疗显著减少了 CCL11 的分泌。PPY-345 治疗并未抑制 NF-κB 向核内易位，但抑制了信号转导和转录激活因子 6（STAT6）的磷酸化。PPY-345 治疗显著降低了全身 plethysmography 测量的气道高反应性。PPY-345 进一步减少了 BAL 液中的总细胞，包括嗜酸性粒细胞、巨噬细胞和淋巴细胞，减少了肺组织中的杯状细胞增生和肌球蛋白轻链 2 阳性平滑肌细胞面积。此外，PPY-345 显著抑制了血清中 OVA-IgE 的水平。这些结果表明 PPY-345 可以改善 OVA 致敏小鼠的哮喘症状。
