Mechanism of skin fibrosis by lipid mediators and its clinical trials

n -甲基乙醇胺（MEA）是乙醇胺的类似物，据报道可减轻大鼠心脏纤维化并降低胶原蛋白含量；然而，人们对其机制知之甚少。因此，我们旨在通过关注人真皮成纤维细胞细胞外基质的产生来确定MEA的抗纤维化作用。MEA在蛋白、mRNA和转录水平上降低了I型胶原蛋白的表达。相反，MEA在蛋白和mRNA水平上增强了基质金属蛋白酶-1 （MMP-1）的表达。MEA不抑制TGF-p的作用，如I型胶原蛋白的产生、结缔组织生长因子（CTGF）的诱导或MMP-1的抑制。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激活了细胞外信号调节激酶1/2 （ERK1/2）和c-Jun n末端激酶（JNK）途径，但抑制了p38丝裂原激活蛋白激酶（p38MAPK）途径。ERK1/2抑制剂降低了MEA对I型胶原基因表达的抑制作用，而JNK抑制剂和p38MAPK抑制剂都不能否定MEA的作用。这些结果表明，MEA通过ERK1/2信号通路抑制I型胶原基因表达。然而，ERK 1/2和JNK抑制剂阻断了MEA介导的MMP-1的诱导，而p38MAPK抑制剂增强了MEA诱导的MMP-1基因的表达。这些结果表明，MEA通过ERK1/2和JNK信号通路增强MMP-1基因的表达，并通过p38 MAPK信号通路抑制MMP-1基因的表达。因此，MEA通过多种途径发挥抗纤维化作用，是治疗以过度ECM沉积为特征的疾病（如硬皮病和瘢痕疙瘩）的有希望的候选药物。

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.