Dasatinib ameliorates chronic pancreatitis induced by caerulein via anti-fibrotic and anti-inflammatory mechanism
Dasatinib ameliorates chronic pancreatitis induced by caerulein via anti-fibrotic and anti-inflammatory mechanism
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达沙替尼通过抗纤维化和抗炎机制改善雨蛙素诱导的慢性胰腺炎
DOI：
10.1016/j.phrs.2019.104357
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发表时间：
2019-09-01
影响因子：
9.3
通讯作者：
Hu, Liang-Hao
中科院分区：
文献类型：
--
作者：
Zeng, Xiang-Peng;Wang, Li-Juan;Hu, Liang-Hao
慢性胰腺炎（CP）的特征在于胰腺的持续炎症和纤维化。到目前为止，没有临床治疗可逆转？炎症性损伤或胰腺纤维化。本研究系统地研究了达沙替尼（一种多种酪氨酸激酶（TK）抑制剂）在体内和体外对胰腺纤维化和炎症的影响。我们发现，达沙替尼显著改善胰腺纤维化和巨噬细胞浸润的雨蛙素诱导的小鼠CP模型。进一步的RNA-seq和磷酸化蛋白质组学分析以及体外验证试验表明，达沙替尼对PSC的增殖和活化具有显著的抑制作用，这可能是由于通过抑制上游多个TK（如PDGFR和Src）和MAPK级联（包括ERK 1/2和p38？MAPK）。此外，达沙替尼显著抑制巨噬细胞的M1和M2极化，并阻止其募集和与PSC的串扰。我们的研究结果表明，达沙替尼是一个潜在的抗炎和抗纤维化治疗策略CP。
Chronic pancreatitis (CP) is characterized by persistent inflammation and fibrosis of the pancreas. To date, no clinical therapy is available to reverse the in?ammatory damage or pancreatic fibrosis associated with CP. This study systematically investigated the effect of Dasatinib, a multiple tyrosine kinases (TKs) inhibitor, on pancreatic fibrosis and inflammation in vivo and in vitro. We found that Dasatinib notably ameliorated pancreatic fibrosis and infiltration of macrophages in a model of caerulein-induced murine CP. Further RNA-seq and phosphoproteomic analysis and in vitro validation assays indicated that Dasatinib exerted a marked inhibition on the proliferation and activation of PSCs, which may be resulted from increased GSK3 beta-mediated beta-catenin cytosol retention by inhibiting upstream multiple TKs (such as PDGFR and Src) and MAPK cascades (including ERK1/2 and p38?MAPK). In addition, Dasatinib significantly restrained both the M1 and M2 polarization of macrophages, and impeded its recruitment and crosstalk with PSCs. Our findings indicated that Dasatinib is a potential anti-inflammatory and anti-fibrotic therapeutic strategy for CP.