TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate
TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate
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DOI：
10.1007/s00011-011-0370-1
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发表时间：
2011-12-01
影响因子：
6.7
通讯作者：
Thorlacius, Henrik
中科院分区：
文献类型：
--
作者：
Awla, Darbaz;Abdulla, Aree;Thorlacius, Henrik
目的中性粒细胞浸润是急性胰腺炎（AP）病理生理的关键调节因子，尽管toll样受体（TLRs）在AP中的作用尚不清楚。本研究的目的是确定TLR2和TLR4在严重AP中白细胞募集和组织损伤中的作用。实验设计在野生型、TLR2和TLR4缺陷小鼠的胰管中逆行输注牛磺酸胆酸钠诱导AP。结果牛磺胆酸盐刺激引起明显的胰腺损伤，表现为腺泡细胞坏死、中性粒细胞浸润、局灶性出血和水肿形成，以及胰腺和血清中血淀粉酶和CXCL2（巨噬细胞炎症蛋白-2）水平升高。此外，牛磺酸胆酸的挑战增加胰蛋白酶原在胰腺中的激活。值得注意的是，TLR2基因缺陷小鼠在牛磺酸胆酸攻毒后表现出与野生型小鼠相似的表型。相比之下，tlr4缺陷小鼠暴露于牛油胆酸后，组织损伤、胰腺和肺髓过氧化物酶（MPO）活性、血清和胰腺CXCL2水平以及血液淀粉酶水平均显著降低。然而，在tlr4缺陷小鼠中，牛磺酸胆碱诱导的胰蛋白酶原激活是完整的。结论我们的数据表明TLR4在小鼠重度AP的发病机制中起作用，而不是TLR2。
Objective Neutrophil infiltration is a key regulator in the pathophysiology of acute pancreatitis (AP), although the impact of Toll-like receptors (TLRs) in AP remains elusive. The aim of this study was to define the role of TLR2 and TLR4 in leukocyte recruitment and tissue damage in severe AP.Experimental design AP was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in wild-type, TLR2-and TLR4-deficient mice. Samples were collected 24 h after induction of AP.Results Taurocholate challenge caused a clear-cut pancreatic damage characterized by increased acinar cell necrosis, neutrophil infiltration, focal hemorrhage and edema formation, as well as increased levels of blood amylase and CXCL2 (macrophage inflammatory protein-2) in the pancreas and serum. Moreover, challenge with taurocholate increased activation of trypsinogen in the pancreas. Notably, TLR2 gene-deficient mice exhibited a similar phenotype to wild-type mice after challenge with taurocholate. In contrast, tissue damage, pancreatic and lung myeloperoxidase (MPO) activity, serum and pancreatic levels of CXCL2 as well as blood amylase were significantly reduced in TLR4-deficient mice exposed to taurocholate. However, taurocholate-induced activation of trypsinogen was intact in TLR4-deficient mice.Conclusion Our data suggest a role for TLR4 but not TLR2 in the pathogenesis of severe AP in mice.