2007 Fiscal Year Final Research Report Summary
Mechanism of skin fibrosis by lipid mediators and its clinical trials
| Project/Area Number |
18591234
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Gunma University |
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Principal Investigator |
ISHIKAWA Osamu Gunma University, graduate school of medicine, Dermatology, Professor (90168188)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Masatoshi Gunma University, graduate school of medicine, Dermatology, Assistant Professor (80302462)
YAMANAKA Masayoshi Gunma University, graduate school of medicine, Dermatology, Assistant Professor (30323364)
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| Project Period (FY) |
2006 – 2007
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| Keywords | fibrosis / signal trunsduction / extracellular matrix / collagen / lipid mediators / TGF-beta / phospholipase / MAP kinase |
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| Research Abstract |
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.
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