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Mechanism of skin fibrosis by lipid mediators and its clinical trials

脂质介质导致皮肤纤维化的机制及其临床试验

基本信息

批准号：
18591234
负责人：
ISHIKAWA Osamu
金额：
$ 2.17万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

N-methylethanolamine (MEA), an analog of ethanolamine, has been reported to attenuate cardiac fibrosis and decrease collagen content in rats; however, the mechanism is poorly understood. We therefore aimed to determine the antifibrotic effect of MEA by focusing on extracellular matrix production in human dermal fibroblasts. MEA reduced the expression of type I collagen at the protein, mRNA, and transcriptional levels. In contrast, MEA enhanced the expression of matrix metalloproteinase-1 (MMP-1) at the protein and mRNA levels. MEA did not inhibit the actions of TGF-p, such as type I collagen production, connective tissue growth factor (CTGF) induction, or MMP-1 suppression. These results indicate that the antifibrotic effect of MEA is independent of TGF-β signaling. MEA activated extracellular signal-regulated kinase-1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways, but suppressed the p38 mitogenactivated protein kinase (p38MAPK) pathway. An ERK1/2 inhibitor diminished the inhibitory effect of MEA on type I collagen gene expression, while both a JNK inhibitor and a p38MAPK inhibitor failed to negate MEA actions. These results suggest that MEA inhibits type I collagen gene expression through ERK1/2 signaling. However, ERK 1/2 and JNK inhibitors blocked the MEA-mediated induction of MMP-1, while p38MAPK inhibitor enhanced MMP-1 gene expression induced by MEA. These results indicate that MEA enhanced MMP-1 gene expression through ERK1/2 and JNK signaling and suppressed it through p38 MAPK signaling. Thus, MEA exerts antifibrotic actions through several pathways and is a promising candidate for the treatment of diseases characterized by excessive ECM deposition, such as scleroderma and keloid.

N-甲基乙醇胺（MEA），乙醇胺的类似物，已被报道，以减轻心脏纤维化和减少胶原蛋白的含量在大鼠;然而，其机制知之甚少。因此，我们的目的是确定MEA的抗纤维化作用，通过关注细胞外基质的生产在人皮肤成纤维细胞。MEA在蛋白质、mRNA和转录水平上降低I型胶原的表达。与此相反，MEA在蛋白和mRNA水平上增强基质金属蛋白酶-1（MMP-1）的表达。MEA不抑制TGF-β的作用，如I型胶原蛋白的产生、结缔组织生长因子（CTGF）诱导或MMP-1抑制。这些结果表明MEA的抗纤维化作用不依赖于TGF-β信号传导。MEA激活细胞外信号调节激酶1/2（ERK 1/2）和c-Jun N-末端激酶（JNK）通路，但抑制p38丝裂原活化蛋白激酶（p38 MAPK）通路。ERK 1/2抑制剂减弱MEA对I型胶原基因表达的抑制作用，而JNK抑制剂和p38 MAPK抑制剂均未能否定MEA的作用。这些结果表明MEA通过ERK 1/2信号传导抑制I型胶原基因表达。ERK 1/2和JNK抑制剂阻断MEA诱导的MMP-1表达，p38 MAPK抑制剂增强MEA诱导的MMP-1表达。这些结果表明，MEA通过ERK 1/2和JNK信号转导增强MMP-1基因表达，并通过p38 MAPK信号转导抑制MMP-1基因表达。因此，MEA通过几种途径发挥抗纤维化作用，并且是用于治疗以过度ECM沉积为特征的疾病如硬皮病和瘢痕疙瘩的有希望的候选物。