p38 Mitogen-Activated Protein Kinase Pathways in Asthma and COPD
p38 Mitogen-Activated Protein Kinase Pathways in Asthma and COPD
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DOI：
10.1378/chest.10-1914
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发表时间：
2011-06-01
期刊：
影响因子：
9.6
通讯作者：
Chung, Kian Fan
中科院分区：
文献类型：
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作者：
Chung, Kian Fan
丝裂原活化蛋白激酶（MAPK）家族包括p38激酶，其由高度保守的脯氨酸导向的丝氨酸-苏氨酸蛋白激酶组成，所述丝氨酸-苏氨酸蛋白激酶响应于炎症信号而被活化。在四种亚型中，p38 α在炎性细胞中最丰富，并且主要通过小分子抑制剂的可用性进行了最多的研究。p38底物包括转录因子;其他蛋白激酶，其进而磷酸化转录因子;细胞骨架蛋白和翻译组分;以及其他酶。哮喘和COPD都以慢性气流阻塞、气道和肺重塑以及慢性炎症为特征。p38通过促炎细胞因子/趋化因子的激活和释放、这些基因的翻译后调节以及炎症细胞迁移的激活参与香烟烟雾暴露、内毒素和氧化应激诱导的炎症反应。抑制p38 MAPK可防止变应原诱导的肺嗜酸性粒细胞增多、粘液高分泌和气道高反应性，这些作用可能部分来自p38激活嗜酸性粒细胞凋亡和气道平滑肌细胞产生细胞因子/趋化因子。此外，p38调节氧化应激诱导的增强的收缩反应。在上皮细胞和巨噬细胞中观察到的p38活化也可能是严重哮喘和COPD的皮质类固醇不敏感性的基础。因此，p38抑制剂对这些病症提供了潜在的有吸引力的治疗。第二代p38抑制剂在治疗类风湿性关节炎方面令人失望。在两项针对COPD患者的6周研究中，结果令人鼓舞。副作用如肝毒性仍然是一种可能性，p38抑制剂的有益作用是否具有临床意义和持续需要确定。胸部2011; 139（6）：1470-1479
The mitogen-activated protein kinase (MAPK) family includes the p38 kinases, which consist of highly conserved proline-directed serine-threonine protein kinases that are activated in response to inflammatory signals. Of the four isoforms, p38 alpha is the most abundant in inflammatory cells and has been the most studied through mainly the availability of small molecule inhibitors. The p38 substrates include transcription factors; other protein kinases, which in turn phosphorylate transcription factors; cytoskeletal proteins and translational components; and other enzymes. Both asthma and COPD are characterized by chronic airflow obstruction, airway and lung remodeling, and chronic inflammation. p38 is involved in the inflammatory responses induced by cigarette smoke exposure, endotoxin, and oxidative stress through activation and release of proinflammatory cytokines/chemokines, posttranslational regulation of these genes, and activation of inflammatory cell migration. Inhibition of p38 MAPK prevented allergen-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness, effects that may partly result from p38 activation on eosinophil apoptosis and on airway smooth muscle cell production of cytokines/chemokines. In addition, p38 regulates the augmented contractile response induced by oxidative stress. The activation of p38 observed in epithelial cells and macrophages also may underlie corticosteroid insensitivity of severe asthma and COPD. Therefore, p38 inhibitors present a potential attractive treatment of these conditions. Second-generation p38 inhibitors have been disappointing in the treatment of rheumatoid arthritis. In two 6-week studies in patients with COPD, the results were encouraging. Side effects such as liver toxicity remain a possibility, and whether the beneficial effects of p38 inhibitors are clinically significant and sustained need to be determined. CHEST 2011; 139(6):1470-1479