Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis.
Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis.
复制标题
DOI：
10.1371/journal.pone.0089114
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ko TC
中科院分区：
文献类型：
--
作者：
Gao X;Cao Y;Staloch DA;Gonzales MA;Aronson JF;Chao C;Hellmich MR;Ko TC
骨形态发生蛋白 (BMP) 在肾脏、肺和肝脏中具有抗纤维化功能。然而，它们在慢性胰腺炎（CP）中的作用尚不清楚。本研究的目的是明确 CP 诱导下 BMP 信号在体内胰腺中的抗纤维化作用。本研究使用 BMP II 型受体 (BMPR2+/-) 缺失的小鼠与野生型小鼠进行比较。采用腹腔重复注射雨蛙素诱导CP，持续4周，并评估CP的严重程度。从小鼠体内分离出胰腺星状细胞 (PSC)，并在体外用 BMP2 和 TGF-β 处理，并测量细胞外基质蛋白 (ECM) 的产生。还评估了 Smad 和丝裂原激活蛋白激酶 (MAPK) 信号传导。与野生型小鼠相比，BMPR2+/- 小鼠在 CP 诱导后显示出更大的胰腺纤维化、PSC 活化和白细胞浸润（P<0.05）。在 CP 诱导下，野生型小鼠中磷酸化 (p)Smad1/5/8 升高，而这种效应在 BMPR2+/- 小鼠中被消除；与野生型小鼠相比，BMPR2+/- 小鼠中的 pSmad2 和 pp38MAPK 进一步增强（P<0.05）。在体外，BMP2 抑制野生型 PSC 中 TGF-β 诱导的 ECM 蛋白纤连蛋白的产生；这种效应在 BMPR2+/- PSC 中被消除（P<0.05）。在 BMPR2+/- PSC 中，与野生型 PSC 相比，BMP2 刺激后几乎检测不到 pSmad1/5/8 水平，而 TGF-β 刺激则进一步增强了 pSmad2 水平（P<0.05）。 BMPR2/Smad1/5/8 信号传导通过抑制 Smad2 和 p38MAPK 信号传导途径，对雨蛙蛋白诱导的胰腺纤维化发挥保护作用。
Bone morphogenetic proteins (BMPs) have an anti-fibrogenic function in the kidney, lung, and liver. However, their role in chronic pancreatitis (CP) is unknown. The aim of this study was to define the anti-fibrogenic role of BMP signaling in the pancreas in vivo under CP induction. Mice with a deletion of BMP type II receptor (BMPR2+/−) were used in this study in comparison with wild-type mice. CP was induced by repetitive cerulein injection intraperitoneally for 4 weeks, and the severity of CP was evaluated. Pancreatic stellate cells (PSCs) were isolated from the mice and treated with BMP2 and TGF-β in vitro, and extracellular matrix protein (ECM) production was measured. Smad and mitogen-activated protein kinase (MAPK) signaling was also evaluated. BMPR2+/− mice revealed a greater pancreatic fibrosis, PSC activation and leukocyte infiltration after CP induction compared to wild-type mice (P<0.05). Under CP induction, phospho (p)Smad1/5/8 was elevated in wild-type mice and this effect was abolished in BMPR2+/− mice; pSmad2 and pp38MAPK were further enhanced in BMPR2+/− mice compared to wild-type mice (P<0.05). In vitro, BMP2 inhibited TGF-β-induced ECM protein fibronectin production in wild-type PSCs; this effect was abolished in BMPR2+/− PSCs (P<0.05). In BMPR2+/− PSCs, pSmad1/5/8 level was barely detectable upon BMP2 stimulation, while pSmad2 level was further enhanced by TGF-β stimulation, compared to wild-type PSCs (P<0.05). BMPR2/Smad1/5/8 signaling plays a protective role against cerulein-induced pancreatic fibrosis by inhibiting Smad2 and p38MAPK signaling pathways.
登录
查看更多内容
DOI：
10.1183/09031936.00011810
发表时间：
2010-10
期刊：
The European respiratory journal
影响因子：
--
作者：
Tarantal AF;Chen H;Shi TT;Lu CH;Fang AB;Buckley S;Kolb M;Gauldie J;Warburton D;Shi W
通讯作者：
Shi W
影响因子：
37.8
作者：
Song, YL;Jones, JE;Zhang, YY
通讯作者：
Zhang, YY
影响因子：
29.4
作者：
Bachem, MG;Schneider, E;Adler, G
通讯作者：
Adler, G
影响因子：
2.7
作者：
Beppu, H;Kawabata, M;Miyazono, K
通讯作者：
Miyazono, K
影响因子：
2.7
作者：
Bush, KT;Sakurai, H;Nigam, SK
通讯作者：
Nigam, SK