Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
PLoS One. 2012;7(9):e46201. doi: 10.1371/journal.pone.0046201. Epub 2012 Sep 27.
Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation-based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 µg/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP.
急性胰腺炎（AP）是一种常见的炎症性疾病，由腺泡细胞损伤和随后的白细胞浸润引起的胰腺炎症介导。神经元导向蛋白 netrin-1 已被证明可控制白细胞迁移，并在几种炎症性疾病中调节炎症反应。本研究旨在研究 netrin-1 在小鼠急性胰腺炎体内模型中的作用。通过两次腹腔内注射 L-精氨酸（4 g/kg）在 C57BL/6 小鼠中诱导 AP。在第二次注射 L-精氨酸后，立即通过尾静脉向小鼠静脉内给予重组小鼠 netrin-1（1 µg/只）或载体（0.1%BSA），此后每 24 小时一次。在胰腺炎诱导后 0 至 96 小时的多个时间间隔处死小鼠。收集血液和胰腺和肺组织样本，以生化和组织学方法确定胰腺炎的严重程度。免疫组织化学染色表明 netrin-1 主要在正常胰腺和 AP 模型胰腺的胰岛细胞中表达，并且在 AP 过程中 netrin-1 的胰腺表达在 mRNA 和蛋白水平均下调。外源性 netrin-1 给药显著降低血浆淀粉酶水平、髓过氧化物酶活性、促炎细胞因子产生以及胰腺和肺组织损伤。此外，netrin-1 给药并未导致核因子-κB 在 L-精氨酸诱导的 AP 中胰腺的激活受到显著抑制。总之，我们的新数据表明，netrin-1 能够改善严重急性胰腺炎小鼠的胰腺和肺损伤，并发挥抗炎作用。因此，我们的结果表明，netrin-1 可能成为 AP 管理的新靶标。
