Department of Respiratory Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, People's Republic of China.
Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, -17177, Stockholm, SE, Sweden.
Respir Res. 2017 Dec 29;18(1):216. doi: 10.1186/s12931-017-0697-4.
Exposure to ambient ozone (O) increases the susceptivity to allergens and triggers exacerbations in patients with asthma. However, the detailed mechanisms of action for O to trigger asthma exacerbations are still unclear.
An ovalbumin (OVA)-established asthmatic mouse model was selected to expose to filtered air (OVA-model) or 1.0 ppm O (OVA-O model) during the process of OVA challenge. Next, the possible involvements of p38 MAPK and oxidative stress in the ozone actions on the asthma exacerbations were investigated on the mice of OVA-O model by treating them with SB239063 (a p38 MAPK inhibitor), and/or the α-tocopherol (antioxidant). Biological measurements were conducted including airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL), inflammation in the airway lumen and lung parenchyma, the phosphorylation of p38 MAPK and heat shock protein (HSP) 27 in the tracheal tissues, and the malondialdehyde (MDA) content and the glutathione peroxidase (GSH-Px) activity in lung tissues.
In OVA-allergic mice, O3 exposure deteriorated airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL) and pulmonary inflammation, accompanied by the increased oxidative stress in lung tissues and promoted p38 MAPK and HSP27 phosphorylation in tracheal tissues. Administration of SB239063 (a p38 MAPK inhibitor) on OVA-O3 model exclusively mitigated the Raw, the CL, and the BAL IL-13 content, while α-tocopherol (antioxidant) differentially reduced the BAL number of eosinophils and macrophages, the content of BAL hyaluronan, the peribronchial inflammation, as well as the mRNA expression of TNF-α and IL-5 in the lung tissues of OVA-O3 model. Administration of these two chemical inhibitors similarly inhibited the AHR, the BAL IFN-γ and IL-6 production, the perivascular lung inflammation and the lung IL-17 mRNA expression of OVA-O3 model. Interestingly, the combined treatment of both compounds together synergistically inhibited neutrophil counts in the BALF and CXCL-1 gene expression in the lung.
O exposure during the OVA challenge process promoted exacerbation in asthma. Both p38 MAPK and oxidative stress were found to play a critical role in this process and simultaneous inhibition of these two pathways significantly reduced the O-elicited detrimental effects on the asthma exacerbation.
暴露于环境臭氧（O）会增加过敏原的敏感性，并引发哮喘患者的恶化。然而，臭氧引发哮喘恶化的详细作用机制仍不清楚。
选择卵清蛋白（OVA）建立的哮喘小鼠模型，在 OVA 挑战过程中暴露于过滤空气（OVA-模型）或 1.0ppm O（OVA-O 模型）。接下来，通过用 SB239063（p38 MAPK 抑制剂）和/或α-生育酚（抗氧化剂）处理 OVA-O 模型的小鼠，研究 p38 MAPK 和氧化应激在臭氧对哮喘恶化作用中的可能参与。进行了包括气道高反应性（AHR）、气道阻力（Raw）、肺顺应性（CL）、气道和肺实质炎症、气管组织中 p38 MAPK 和热休克蛋白（HSP）27 的磷酸化、肺组织中丙二醛（MDA）含量和谷胱甘肽过氧化物酶（GSH-Px）活性在内的生物学测量。
在 OVA 过敏小鼠中，O3 暴露恶化了气道高反应性（AHR）、气道阻力（Raw）、肺顺应性（CL）和肺部炎症，同时肺组织中氧化应激增加，并促进了气管组织中 p38 MAPK 和 HSP27 的磷酸化。在 OVA-O3 模型上单独给予 SB239063（p38 MAPK 抑制剂）可减轻 Raw、CL 和 BALIL-13 含量，而 α-生育酚（抗氧化剂）则可降低 BAL 嗜酸性粒细胞和巨噬细胞数量、BAL 透明质酸含量、支气管周围炎症以及 OVA-O3 模型肺组织中 TNF-α 和 IL-5 的 mRNA 表达。给予这两种化学抑制剂同样抑制了 OVA-O3 模型的 AHR、BALIFN-γ 和 IL-6 的产生、血管周围肺炎症和肺 IL-17mRNA 表达。有趣的是，两种化合物的联合治疗协同抑制了 BALF 中的中性粒细胞计数和肺中的 CXCL-1 基因表达。
在 OVA 挑战过程中暴露于 O 会促进哮喘恶化。发现 p38 MAPK 和氧化应激在这个过程中起着关键作用，同时抑制这两个途径显著减少了 O 对哮喘恶化的有害影响。
