Department of Surgery, University of Texas Health Science Center-Houston, Houston, TX 77026, USA.
Am J Physiol Gastrointest Liver Physiol. 2013 May 1;304(9):G804-13. doi: 10.1152/ajpgi.00306.2012. Epub 2013 Feb 21.
Activation of pancreatic stellate cells (PSCs) by transforming growth factor (TGF)-β is the key step in the development of pancreatic fibrosis, a common pathological feature of chronic pancreatitis (CP). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have anti-fibrogenic functions, in contrast to TGF-β, in the kidney, lung, and liver. However, it is not known whether BMPs have an anti-fibrogenic role in the pancreas. The current study was designed to investigate the potential anti-fibrogenic role of BMPs in the pancreas using an in vivo CP model and an in vitro PSC model. CP was induced by repetitive intraperitoneal injections of cerulein in adult Swiss Webster mice. The control mice received saline injections. Compared with the control, cerulein injections induced a time-dependent increase in acinar injury and progression of fibrosis and a steady increase in inflammation. Cerulein injections also induced increases of the extracellular matrix (ECM) protein fibronectin and of α-smooth muscle actin (α-SMA)-positive stellate cells (PSCs). The mice receiving cerulein injections showed increased BMP2 protein levels and phosphorylated Smad1 levels up to 4 wk and then declined at 8 wk to similar levels as the control. In vitro, the isolated mouse and human PSCs were cultured and pretreated with BMP2 followed by TGF-β treatment. BMP2 pretreatment inhibited TGF-β-induced α-SMA, fibronectin, and collagen type Ia expression. Knocking down Smad1 with small-interfering RNA reversed the inhibitory effect of BMP2 on TGF-β-induced α-SMA and fibronectin expression. Thus, BMP2 opposes the fibrogenic function of TGF-β in PSCs through the Smad1 signaling pathway.
转化生长因子 (TGF)-β 激活胰腺星状细胞 (PSCs) 是胰腺纤维化发展的关键步骤，胰腺纤维化是慢性胰腺炎 (CP) 的共同病理特征。骨形态发生蛋白 (BMPs) 是 TGF-β 超家族的成员，与 TGF-β 相反，在肾脏、肺部和肝脏中具有抗纤维化功能。然而，BMPs 在胰腺中是否具有抗纤维化作用尚不清楚。本研究旨在通过体内 CP 模型和体外 PSC 模型研究 BMPs 在胰腺中的潜在抗纤维化作用。CP 通过在成年瑞士 Webster 小鼠中重复腹腔内注射 cerulein 诱导。对照组小鼠接受生理盐水注射。与对照组相比，cerulein 注射诱导了时间依赖性的腺泡损伤和纤维化进展以及炎症的持续增加。cerulein 注射还诱导细胞外基质 (ECM) 蛋白纤维连接蛋白和α-平滑肌肌动蛋白 (α-SMA)-阳性星状细胞 (PSCs) 的增加。接受 cerulein 注射的小鼠显示 BMP2 蛋白水平和磷酸化 Smad1 水平在 4 周内持续增加，然后在 8 周时下降至与对照组相似的水平。在体外，分离的小鼠和人 PSCs 被培养并在用 TGF-β 处理之前用 BMP2 预处理。BMP2 预处理抑制了 TGF-β 诱导的 α-SMA、纤维连接蛋白和胶原 Iα 的表达。用小干扰 RNA 敲低 Smad1 逆转了 BMP2 对 TGF-β 诱导的 α-SMA 和纤维连接蛋白表达的抑制作用。因此，BMP2 通过 Smad1 信号通路拮抗 TGF-β 在 PSCs 中的纤维化功能。
