Emerging role of MAP kinase pathways as therapeutic targets in COPD.
Emerging role of MAP kinase pathways as therapeutic targets in COPD.
复制标题
DOI：
10.2147/copd.2006.1.2.137
复制
发表时间：
2006
影响因子：
2.8
通讯作者：
D'Armiento JM
中科院分区：
文献类型：
--
作者：
Mercer BA;D'Armiento JM
对慢性阻塞性肺疾病患者肺组织和呼吸道炎症和蛋白酶产生的细胞机制的研究揭示了基于激酶的信号级联反应的重要作用。这些途径可被环境刺激(如烟草烟雾)以及内源性信号(如细胞因子、生长因子和炎症衍生的氧化剂)激活。三个最广泛表征的级联通路是由经典的丝裂原活化蛋白(MAP)激酶(ERK1/2)、应激活化蛋白激酶/c-jun氨基末端蛋白激酶和p38酶调控的。这些磷酸化级联反应通过细胞质传递和放大细胞外受体介导的信号，激活核转录因子，结合并诱导靶基因的表达。其结果是严格控制不同的细胞事件，并对外部刺激做出快速反应。然而，最近的研究表明，MAP激酶的结构性或异常激活与COPD相关的几种表型有关，包括粘液过度生产和分泌、炎症、细胞因子表达、细胞凋亡、T细胞激活、基质金属蛋白酶的产生和纤维化。本文就MAPK信号通路在COPD发病机制中的生物学作用、吸烟对MAPK信号通路的激活以及MAPK抑制剂在COPD治疗中的潜在作用进行综述。
Studies examining the cellular mechanisms of inflammation and protease production in the lung tissue and airways of COPD patients have shed light on the important role of kinase-based signaling cascades. These pathways can be activated by environmental stimuli such as tobacco smoke, and by endogenous signals such as cytokines, growth factors, and inflammation-derived oxidants. The three most widely characterized cascades are those directed by the classical mitogen activated protein (MAP) kinase (ERK1/2), stress activated protein kinase/c-Jun N-terminal protein kinase, and p38 enzymes. These phosphorylation cascades transmit and amplify extracellular, receptor-mediated signals through the cytoplasm of the cell to activate nuclear transcription factors which bind and induce expression of target genes. The result is tight control of diverse cellular events, and rapid responses to external stimuli. However, recent research suggests that constitutive or aberrant activation of MAP kinases contributes to several COPD-associated phenotypes, including mucus overproduction and secretion, inflammation, cytokine expression, apoptosis, T cell activation, matrix metalloproteinase production, and fibrosis. This review explores the biological functions of the MAP kinase pathways in the pathogenesis of COPD, their activation by cigarette smoke, and discusses the potential role of MAP kinase inhibitors in COPD therapy.