Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy.
Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy.
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DOI：
10.1097/mpa.0b013e31825b9f2c
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发表时间：
2013-03
期刊：
影响因子：
2.9
通讯作者：
Ko TC
中科院分区：
文献类型：
--
作者：
Cao Y;Yang W;Tyler MA;Gao X;Duan C;Kim SO;Aronson JF;Popov V;Takahashi H;Saito H;Evers BM;Chao C;Hellmich MR;Ko TC
目的探讨内源性骨形态发生蛋白(BMP)拮抗剂noggin在急性胰腺炎(AP)模型中的作用。每小时一次注射雨蛙素(50µg/kg)诱发急性胰腺炎。对照组小鼠接受了PBS注射。另一组在AP诱导前1小时、AP诱导后2小时、4小时和6小时分别给予Nogin(0.5 mg/kg)。AP诱导完成后1h处死小鼠。采集血样和胰腺进行分析。分离的正常小鼠胰腺腺泡细胞和AR42J细胞分别用BMP2和雨蛙素处理。同时用Noggin处理AR42J细胞。检测Smad1/5/8的磷酸化水平。BMP信号在AP小鼠胰腺中表达上调。BMP2和雨蛙素可诱导腺泡细胞Smad1/5/8的磷酸化，该作用可被noggin阻断。体内应用noggin可抑制AP诱导，减少腺泡细胞空泡形成，阻断Lc3-II水平，部分恢复Beclin-1和Lamp-2水平。BMP信号似乎促进了AP的诱导和自噬，我们的研究表明，noggin可以改善AP并部分恢复自噬稳态。
To investigate the role of bone morphogenetic protein (BMP) signaling in acute pancreatitis (AP) by administration of noggin, an endogenous BMP antagonist, in a cerulein-induced AP model. AP was induced by 9 hourly intraperitoneal injections of cerulein (50 µg/kg). Control mice received PBS injections. In a separate group, noggin (0.5 mg/kg) was given intraperitoneally at 1 hour before, and 2, 4, and 6 hours after AP induction. The mice were euthanized at one hour after completion of AP induction. The blood samples and the pancreas were harvested for analysis. Isolated pancreatic acini from normal mice and AR42J cells were treated with BMP2 and cerulein. AR42J cells were also treated with noggin. Phosphorylation of Smad1/5/8 was measured. BMP signaling was upregulated in AP mouse pancreas. BMP2 and cerulein induced phosphorylation of Smad1/5/8 in the acinar cells in vitro, which was blocked by noggin. Noggin administration in vivo attenuated AP induction, decreased vacuole formation in acinar cells, blocked LC3-II levels and partially restored Beclin-1 and Lamp-2 levels. BMP signaling appears to promote AP induction and autophagy, as suggested by our study showing that noggin ameliorates AP and partially restores autophagic homeostasis.