IS-741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats
IS-741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats
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DOI：
10.1097/mpa.0b013e31802fc1fa
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发表时间：
2007-04-01
期刊：
影响因子：
2.9
通讯作者：
Takayanagi, Ryoichi
中科院分区：
文献类型：
--
作者：
Kaku, Toyoma;Oono, Takamasa;Takayanagi, Ryoichi
目的：慢性胰腺炎是由大量白细胞浸润和纤维化组成的。据报道IS-741是一种通过抑制细胞粘附作用的抗肿瘤药物。在这项研究中，我们研究了IS-741是否可以通过单核细胞浸润抑制胰腺纤维化的进展。方法：采用二丁基二氯化锡诱导大鼠慢性胰腺炎模型，观察IS-741对大鼠胰腺星状细胞（PSC）的影响。二丁基二氯化锡给药后第7 - 28天，给予IS-741或蒸馏水。在第14天和第28天，进行组织学[苏木精-伊红染色和ED 1和平滑肌肌动蛋白（α-SMA）的免疫染色]和生化评价（胰腺内淀粉酶、蛋白质、细胞因子、趋化因子和α-SMA）。在体外，将大鼠PSCs与细胞因子、趋化因子和生长因子同时与IS-741孵育，检测其增殖和活化。结果：组织学上，IS-741可抑制胰腺纤维化，减少ED 1和α-SMA阳性细胞的数量。胰腺内细胞因子、趋化因子和α-SMA的表达也降低。在体外，IS-741对PSCs.Conclusions的增殖，α-SMA表达和胶原蛋白合成没有直接影响：这些结果表明，IS-741抑制巨噬细胞浸润和随后的胰腺纤维化和单核细胞浸润到胰腺是必不可少的胰腺纤维化。
Objectives: Chronic pancreatitis consists of excessive leukocyte infiltration and fibrosis. IS-741 has been reported to be an antiinflammatory drug through an inhibitory action on cell adhesion. In this study, we investigated whether IS-741 could inhibit the progression of pancreatic fibrosis through monocyte infiltration. Moreover, we investigated the effect of IS-741 on rat pancreatic stellate cells (PSCs).Methods: Chronic pancreatitis was induced by dibutyltin dichloride in rats. From days 7 to 28 after dibutyltin dichloride application, IS-741 or distilled water was administered. At days 14 and 28, histological [hematoxylin-eosin stain and immunostain for ED1 and a smooth muscle actin (alpha-SMA)] and biochemical evaluations (intrapancreatic amylase, protein, cytokines, chemokines, and alpha-SMA) were performed. In vitro, rat PSCs were incubated with cytokine, chemokine, and growth factor simultaneously with IS-741, and their proliferation and activation were examined.Results: Histologically, IS-741 inhibited pancreatic fibrosis and decreased the number of ED1- and alpha-SMA-positive cells. The intrapancreatic expression of cytokines, chemokine, and alpha-SMA were also decreased. In vitro, IS-741 has no direct effect on the proliferation, alpha-SMA expression, and collagen synthesis of PSCs.Conclusions: These results suggest that IS-741 suppressed macrophage infiltration and subsequent pancreatic fibrosis and that the infiltration of monocytes into pancreas is essential for pancreatic fibrosis.