Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury.
Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury.
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DOI：
10.1111/hepr.12411
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Bansal MB
中科院分区：
文献类型：
--
作者：
Saiman Y;Jiao J;Fiel MI;Friedman SL;Aloman C;Bansal MB
肝星状细胞的活化和慢性炎症的发展是肝纤维化进展的两个关键特征。我们已经表明，在体外活化的星状细胞增加其表达的CXCL 12以及受体CXCR 4和受体的参与促进促纤维化表型。此外，损伤促进CXCL 12的肝表达增加以及表达CXCR 4的白细胞、粒细胞和髓样细胞的大量浸润。炎性细胞积聚的主要部位在富含CXCL 12的汇管区周围和纤维化间隔内，表明CXCR 4在损伤期间的作用。为了表征肝损伤期间CXCR 4/CXCL 12趋化因子轴的相关性，我们在慢性和急性肝损伤模型中使用CXCR 4小分子抑制剂AMD 3100抑制该轴。在给予和不给予AMD 3100的情况下，对小鼠进行急性和慢性CCl 4肝损伤。肝损伤程度，纤维化，肝内炎症反应的组成进行了表征。在慢性CCl 4肝损伤模型中，用AMD 3100处理小鼠导致肝脏炎症和纤维化增加，肝内中性粒细胞特异性增加。此外，在CCl 4诱导的肝损伤急性模型中，AMD 3100导致肝内中性粒细胞数量增加，并有坏死恶化的趋势。总之，这些数据表明，CXCR 4/CXCL 12趋化因子轴的抑制通过调节肝脏炎症反应是有害的，并且该轴可能在肝损伤中起保护作用。
Activation of hepatic stellate cells and development of chronic inflammation are two key features in the progression of hepatic fibrosis. We have shown that in vitro activated stellate cells increase their expression of CXCL12 as well as the receptor CXCR4 and that receptor engagement promotes a profibrogenic phenotype. Furthermore, injury promotes increased hepatic expression of CXCL12 and a massive infiltration of CXCR4-expressing leukocytes, granulocytes, and myeloid cells. The primary site of inflammatory cell accumulation is around the CXCL12-rich portal tracts and within fibrotic septae, indicating a role for CXCR4 during injury. In order to characterize the relevance of the CXCR4/CXCL12 chemokine axis during hepatic injury we inhibited the axis using AMD3100, a CXCR4 small molecule inhibitor, in models of chronic and acute liver injury. Mice were subjected to acute and chronic CCl4 liver injury with and without AMD3100 administration. The degree of liver injury, fibrosis, and the composition of the intrahepatic inflammatory response were characterized. Treatment of mice with AMD3100 in the chronic CCl4 model of liver injury led to an increase in hepatic inflammation and fibrosis with a specific increase in intrahepatic neutrophils. Furthermore, in an acute model of CCl4 induced liver injury, AMD3100 led to an increase in the number of intrahepatic neutrophils and a trend towards worse necrosis. Together, this data suggests that inhibition of the CXCR4/CXCL12 chemokine axis is injurious through modulation of the hepatic inflammatory response and that this axis may serve a protective role in liver injury.
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影响因子：
29.4
作者：
Harb R;Xie G;Lutzko C;Guo Y;Wang X;Hill CK;Kanel GC;DeLeve LD
通讯作者：
DeLeve LD
影响因子：
6
作者：
McCandless, Erin E.;Piccio, Laura;Klein, Robyn S.
通讯作者：
Klein, Robyn S.
DOI：
10.1016/j.bbrc.2006.11.149
发表时间：
2007-02-02
影响因子：
3.1
作者：
Mehrad, Borna;Burdick, Marie D.;Strieter, Robert M.
通讯作者：
Strieter, Robert M.
影响因子：
4.4
作者：
Ajuebor, MN;Hogaboam, CM;Swain, MG
通讯作者：
Swain, MG
影响因子：
1.5
作者：
Stroncek, DF;Clay, ME;McCullough, J
通讯作者：
McCullough, J