MAPK signalling pathways as molecular targets for anti-inflammatory therapy - from molecular mechanisms to therapeutic benefits
MAPK signalling pathways as molecular targets for anti-inflammatory therapy - from molecular mechanisms to therapeutic benefits
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DOI：
10.1016/j.bbapap.2005.08.017
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发表时间：
2005-12-30
影响因子：
3.2
通讯作者：
Kaminska, B
中科院分区：
文献类型：
--
作者：
Kaminska, B
过度炎症已被认为是许多人类疾病的关键因素，包括炎症和自身免疫性疾病、神经退行性疾病、感染、心血管疾病和癌症。脑缺血和神经退行性疾病伴随着显著的炎症反应，炎症反应由细胞因子、黏附分子和其他炎症介质的表达启动，包括前列腺素和一氧化氮。本文就炎症的有害影响、炎症信号通路在各种疾病中的调控以及抗炎治疗的潜在分子靶点等方面的最新进展进行了综述。丝裂原活化蛋白激酶(MAPKs)是一类丝氨酸/苏氨酸蛋白激酶家族，介导基本的生物过程和细胞对外界应激信号的反应。MAPK，尤其是p38MAPK的活性增强，参与了转录和翻译水平的炎症介质合成的调节，使其成为抗炎治疗的潜在靶点。针对p38 MAPK和JNK通路的抑制剂已经被开发出来，临床前数据表明它们具有抗炎活性。这篇综述讨论了这些新药如何调节p38 MAPK和JNK信号通路的活性，并在临床前疾病模型中表现出抗炎作用，主要是通过抑制炎症介质的表达。MAPK抑制剂的使用成为一种有吸引力的策略，因为它们能够减少促炎细胞因子的合成及其信号传递。此外，这些药物中有许多是可以口服的小分子药物，临床试验的初步结果表明，这些药物对慢性炎症性疾病患者有临床疗效。(C)2005 Elsevier B.V.保留所有权利。
Excessive inflammation is becoming accepted as a critical factor in many human diseases, including inflammatory and autoimmune disorders, neurodegenerative conditions, infection, cardiovascular diseases, and cancer. Cerebral ischemia and neurodegenerative diseases are accompanied by a marked inflammatory reaction that is initiated by expression of cytokines, adhesion molecules, and other inflammatory mediators, including prostanoids and nitric oxide. This review discusses recent advances regarding the detrimental effects of inflammation, the regulation of inflammatory signalling pathways in various diseases, and the potential molecular targets for anti-inflammatory therapy. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases that mediate fundamental biological processes and cellular responses to external stress signals. Increased activity of MAPK, in particular p38 MAPK, and their involvement in the regulation of the synthesis of inflammation mediators at the level of transcription and translation, make them potential targets for anti-inflammatory therapeutics. Inhibitors targeting p38 MAPK and JNK pathways have been developed, and preclinical data suggest that they exhibit anti-inflammatory activity. This review discusses how these novel drugs modulate the activity of the p38 MAPK and JNK signalling cascades, and exhibit anti-inflammatory effects in preclinical disease models, primarily through the inhibition of the expression of inflammatory mediators. Use of MAPK inhibitors emerges as an attractive strategy because they are capable of reducing both the synthesis of pro-inflammatory cytokines and their signalling. Moreover, many of these drugs are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disease. (c) 2005 Elsevier B.V. All rights reserved.