Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis
Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis
复制标题
DOI：
10.1136/gut.2005.064543
复制
发表时间：
2006-01-01
期刊：
影响因子：
24.5
通讯作者：
Apte, MV
中科院分区：
文献类型：
--
作者：
McCarroll, JA;Phillips, PA;Apte, MV
背景和目的：激活的胰腺星状细胞（PSC）参与酒精诱导的胰腺纤维化的产生。PSC激活总是与细胞质维生素A（视黄醇）储存的损失有关。此外，众所周知，视黄醇和乙醇通过类似的途径代谢。我们的小组和其他人已经证明，乙醇诱导的PSC激活是由丝裂原活化蛋白激酶（MAPK）途径介导的，但视黄醇及其代谢产物全反式维甲酸（ATRA）和9-顺式维甲酸（9-RA）在PSC静止/激活中的具体作用，或其对乙醇诱导的PSC激活的影响尚不清楚。因此，本研究的目的是（i）检查视黄醇、ATRA和9-RA对PSC活化的影响;（ii）确定视黄醇、ATRA和9-RA是否影响PSC中的MAPK信号传导;和（iii）评估补充视黄醇对由乙醇活化的PSC的影响。㈠扩散;（ii）平滑肌肌动蛋白（α-SMA）、胶原蛋白I、纤连蛋白和层粘连蛋白的表达;和（iii）MAPK（细胞外调节激酶1和2、p38激酶和c-Jun N末端激酶）的活化。还通过在存在或不存在视黄醇的情况下将细胞与乙醇一起孵育5天来检查视黄醇对用乙醇处理的PSC的影响，随后评估α-SMA、胶原蛋白I、纤连蛋白和层粘连蛋白的表达。（i）细胞增殖，（ii）α-SMA、胶原I、纤连蛋白和层粘连蛋白的表达，和（iii）所有三类MAPK的活化。此外，视黄醇防止乙醇诱导的PSC活化，如抑制乙醇诱导的α-SMA，胶原蛋白I，纤连蛋白，和层粘连蛋白expression.Conclusions的增加所示：视黄醇及其代谢产物ATRA和9-RA诱导静止与所有三类MAPKs在PSC中的激活显着减少的文化激活的PSC。乙醇诱导的PSC活化可通过补充视黄醇来预防。
Background and aims: Activated pancreatic stellate cells (PSCs) are implicated in the production of alcohol induced pancreatic fibrosis. PSC activation is invariably associated with loss of cytoplasmic vitamin A ( retinol) stores. Furthermore, retinol and ethanol are known to be metabolised by similar pathways. Our group and others have demonstrated that ethanol induced PSC activation is mediated by the mitogen activated protein kinase (MAPK) pathway but the specific role of retinol and its metabolites all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-RA) in PSC quiescence/activation, or its influence on ethanol induced PSC activation is not known. Therefore, the aims of this study were to (i) examine the effects of retinol, ATRA, and 9-RA on PSC activation; (ii) determine whether retinol, ATRA, and 9-RA influence MAPK signalling in PSCs; and (iii) assess the effect of retinol supplementation on PSCs activated by ethanol.Methods: Cultured rat PSCs were incubated with retinol, ATRA, or 9-RA for varying time periods and assessed for: (i) proliferation; (ii) expression of a smooth muscle actin (alpha-SMA), collagen I, fibronectin, and laminin; and (iii) activation of MAPKs (extracellular regulated kinases 1 and 2, p38 kinase, and c-Jun N terminal kinase). The effect of retinol on PSCs treated with ethanol was also examined by incubating cells with ethanol in the presence or absence of retinol for five days, followed by assessment of alpha-SMA, collagen I, fibronectin, and laminin expression.Results: Retinol, ATRA, and 9- RA significantly inhibited: (i) cell proliferation, (ii) expression of alpha-SMA, collagen I, fibronectin, and laminin, and (iii) activation of all three classes of MAPKs. Furthermore, retinol prevented ethanol induced PSC activation, as indicated by inhibition of the ethanol induced increase in alpha-SMA, collagen I, fibronectin, and laminin expression.Conclusions: Retinol and its metabolites ATRA and 9-RA induce quiescence in culture activated PSCs associated with a significant decrease in the activation of all three classes of MAPKs in PSCs. Ethanol induced PSC activation is prevented by retinol supplementation.