Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice
Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice
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DOI：
10.1089/ars.2006.8.1835
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发表时间：
2006-09-01
影响因子：
6.6
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Ohashi, Shinya;Nishio, Akiyoshi;Chiba, Tsutomu
慢性胰腺炎（CP）是胰腺反复损伤的结果，其发病机制与多种促炎细胞因子和趋化因子的持续产生密切相关。单核细胞趋化蛋白1（MCP-1）是CC趋化因子家族的成员，被认为通过单核细胞/巨噬细胞募集促进CP的进展。本研究旨在阐明硫氧还蛋白-1（TRX-1），一种具有抗氧化活性的氧化还原调节蛋白，在MCP-1产生和胰腺纤维化中的保护作用，使用过表达TRX-1的转基因小鼠（TRX-1-TG小鼠）和野生型C57 BL/6小鼠的CP模型。实验CP是通过重复施用雨蛙肽和脂多糖6周来诱导的。在TRX-1-TG小鼠中，胰腺萎缩得到改善，组织学可检测到的炎性细胞浸润、腺萎缩和假管状复合体形成受到抑制。TRX-1的过表达也减弱胰腺纤维化和抑制胰腺星状细胞的活化。与野生型小鼠相比，TRX-1-TG小鼠中MCP-1的血清水平和转化生长因子-β、血小板衍生生长因子和MCP-1的胰腺表达降低。过表达TRX-1也减少了H2 O2诱导的胰腺腺泡细胞中MCP-1的产生。这些结果表明，TRX-1可以通过抑制氧化应激和MCP-1介导的慢性炎症来潜在地减轻胰腺纤维化。
Chronic pancreatitis (CP) is considered to result from repetitive pancreatic injury, and sustained production of various proinflammatory cytokines and chemokines are closely involved in its pathogenesis. Monocyte chemoattractant protein 1 (MCP-1), a member of the CC chemokine family, is believed to contribute to the progression of CP through monocyte/macrophage recruitment. This study aimed to clarify the protective role of thioredoxin-1 (TRX-1), a redox-regulating protein with antioxidative activity, in MCP-1 production and pancreatic fibrosis using a CP model in transgenic mice overexpressing TRX-1 (TRX-1-TG mice) and wildtype C57BL/6 mice. Experimental CP was induced by repeated administration of cerulein and lipopolysaccharide for 6 weeks. In TRX-1-TG mice, pancreatic atrophy was ameliorated, and histologically detectable inflammatory cell infiltration, glandular atrophy, and pseudotubular complex formation were suppressed. Overexpression of TRX-1 also attenuated pancreatic fibrosis and suppressed the activation of pancreatic stellate cells. Serum levels of MCP-1 and pancreatic expression of transforming growth factor-beta, platelet-derived growth factor, and MCP-1 were reduced in TRX-1-TG mice compared with levels in wild-type mice. Overexpression of TRX-1 also reduced H2O2-induced MCP-1 production in isolated pancreatic acinar cells. These results indicate that TRX-1 can potentially attenuate pancreatic fibrosis via the suppression of oxidative stress and MCP-1-mediated chronic inflammation.