Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China; Department of Respiratory Medicine, the Affiliated Hospital of Xuzhou Medical College, 99 Huaihai West Road, Xuzhou, Jiangsu 221000, China.
Free Radic Biol Med. 2016 Dec;101:163-175. doi: 10.1016/j.freeradbiomed.2016.09.012. Epub 2016 Oct 13.
In the pathophysiology of asthma, structural cell dysfunction and concomitant microenvironment changes in airways are crucial to pathological progression, which involves oxidative stress. Caffeic acid phenethyl ester (CAPE) is an active anti-oxidative component obtained from propolis, and has been shown to have beneficial effects on several respiratory disorders, such as chronic obstructive pulmonary disease and lung cancer. However, the impact of CAPE on asthma is not well understood. Therefore, this study investigated the advantages of using CAPE to treat asthma and demonstrated the roles of CAPE in the regulation of airway microenvironments. In ovalbumin (OVA)-sensitized mice, CAPE treatments notably reduced airway hyperresponsiveness, attenuated extensive inflammatory cell infiltration and inhibited goblet cell hyperplasia and collagen deposition and fibrosis. In addition, CAPE improved the airway microenvironment in a dose-dependent manner by inhibiting OVA-induced increases in immunoglobulin E, tumor necrosis factor alpha (TNF-α), transforming growth factor-β1 (TGF-β1), interleukin (IL)-4 and IL-13 and suppressing matrix metalloproteinase-9 and alpha-smooth muscle actin expression as well as malondialdehyde production. To determine the underlying mechanisms responsible for these effects, we used TNF-α-stimulated BECs and TGF-β1-challenged human ASMCs to explore the impacts of CAPE on pro-inflammatory proteins and ASMC proliferation. The results indicated that CAPE significantly limited the secretion of eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1 and dramatically inhibited the proliferation of ASMCs. These effects were shown to be associated with decreased reactive oxidant species (ROS) levels. The phosphorylation of Akt and Mitogen-Activated Protein Kinase (MAPK) caused by increased ROS was significantly decreased by CAPE, which implied a contribution of ROS-MAPK/Akt signaling to the attenuation of asthma. Our findings indicated for the first time that CAPE alleviates airway inflammation and remodeling in chronic asthma by balancing the airway microenvironment, which highlights a novel profile of CAPE as a potent agent for asthma management.
在哮喘的病理生理学中，结构细胞功能障碍和伴随的气道微环境变化对于病理性进展至关重要，其中涉及氧化应激。咖啡酸苯乙酯（CAPE）是一种从蜂胶中提取的活性抗氧化成分，已被证明对几种呼吸系统疾病具有有益作用，如慢性阻塞性肺疾病和肺癌。然而，CAPE 对哮喘的影响尚不清楚。因此，本研究探讨了使用 CAPE 治疗哮喘的优势，并证明了 CAPE 在调节气道微环境中的作用。在卵清蛋白（OVA）致敏的小鼠中，CAPE 治疗显著降低气道高反应性，减轻广泛的炎症细胞浸润，并抑制杯状细胞增生和胶原沉积及纤维化。此外，CAPE 通过抑制 OVA 诱导的免疫球蛋白 E、肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）、白细胞介素（IL）-4 和 IL-13 的增加以及抑制基质金属蛋白酶-9 和α-平滑肌肌动蛋白表达以及丙二醛产生，以剂量依赖的方式改善气道微环境。为了确定这些作用的潜在机制，我们使用 TNF-α 刺激的 BECs 和 TGF-β1 挑战的人 ASMCs 来探索 CAPE 对促炎蛋白和 ASMC 增殖的影响。结果表明，CAPE 显著限制了嗜酸性粒细胞趋化蛋白-1、单核细胞趋化蛋白-1、IL-8 和细胞间黏附分子-1 的分泌，并显著抑制了 ASMC 的增殖。这些作用与活性氧（ROS）水平降低有关。ROS 增加引起的 Akt 和丝裂原激活蛋白激酶（MAPK）的磷酸化被 CAPE 显著降低，这表明 ROS-MAPK/Akt 信号通路参与了哮喘的减轻。我们的研究结果首次表明，CAPE 通过平衡气道微环境来减轻慢性哮喘中的气道炎症和重塑，这突显了 CAPE 作为一种有效的哮喘管理药物的新特性。
