Fibromodulin is upregulated by oxidative stress through the MAPK/AP-1 pathway to promote pancreatic stellate cell activation

被引：25

作者：

An, Wei ^{[1
]}

Zhu, Jian-wei ^{[2
]}

Jiang, Fei ^{[1
]}

Jiang, Hui ^{[3
]}

Zhao, Jiu-long ^{[1
]}

Liu, Mu-yun ^{[1
]}

Li, Gui-xiang ^{[1
]}

Shi, Xin-gang ^{[1
]}

Sun, Chang ^{[1
]}

Li, Zhao-shen ^{[1
]}

机构：

[1] Second Mil Med Univ, Changhai Hosp, Dept Gastroenterol, 168 Changhai Rd, Shanghai 200433, Peoples R China

[2] Soochow Univ, Affiliated Hosp 2, Dept Gastroenterol, 1055 Sanxiang Rd, Suzhou 215008, Peoples R China

[3] Second Mil Med Univ, Changhai Hosp, Dept Pathol, 168 Changhai Rd, Shanghai 200433, Peoples R China

来源：

PANCREATOLOGY | 2020年 / 20卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Fibromodulin; Oxidative stress; MAPK; Activator protein-1; Pancreatic stellate cells; Chronic pancreatitis; PROTEIN-KINASES; PROTEOGLYCANS; FIBROSIS;

D O I：

10.1016/j.pan.2019.09.011

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background/Objectives: Fibromodulin (FMOD) expression in chronic pancreatitis (CP) tissues and its effect on PSC was unknown. Our aim was to investigate the role of FMOD in regulating PSC profibrogenic phenotype and the molecular mechanism of CP. Methods: Rat CP models were induced by dibutyltin dichloride. Pancreatic fibrosis was evaluated by Sirius Red staining. The expression of FMOD and alpha-SMA was measured, the correlation between FMOD expression and fibrosis was investigated in CP models and CP patients. The effects of FMOD on PSCs were examined by CCK-8 and migration assays. We investigated the mechanisms underlying FMOD expression using MND and a MAPK pathway inhibitor. Luciferase reporter and chromatin immunoprecipitation assays were used to investigate the effects of AP-1 on FMOD expression. Results: Sirius Red staining revealed high collagen deposition in model rats. Higher expression of FMOD and alpha-SMA was observed in fibrotic tissues, and the expression of FMOD was correlated with that of alpha-SMA and the areas of Sirius Red staining. Upregulation of FMOD increased the expression of collagen I and alpha-SMA and the proliferation and migration of PSCs. MND induced FMOD and alpha-SMA expression, and knockdown of FMOD abated alpha-SMA expression. ERK and JNK inhibitors attenuated FMOD expression as induced by MND. AP-1 upregulated the expression of FMOD. AP-1 binds to the FMOD promoter and transcriptionally regulates FMOD expression. Conclusion: FMOD levels are upregulated in fibrosis tissues in CP and it is a critical downstream mediator of oxidative stress. FMOD induces PSC activation and maintains the fibrosis phenotype of PSCs. (C) 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.

引用

页码：278 / 287

页数：10

共 33 条

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