Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation.
Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation.
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DOI：
10.1007/s10753-011-9297-5
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发表时间：
2012-02
期刊：
影响因子：
5.1
通讯作者：
Cook, James A.
中科院分区：
文献类型：
--
作者：
Fan, Hongkuan;Wong, Donald;Ashton, Sarah H.;Borg, Keith T.;Halushka, Perry V.;Cook, James A.
趋化因子CXC受体4（CXCR 4）由基质细胞衍生因子（SDF-1α）激活。CXCR 4可能是脂多糖（LPS）感应共簇复合物的一部分，可调节TLR 4活化，有证据表明SDF-1α可激活抗炎信号通路并抑制炎症。在本研究中，我们检查了SDF-1α肽类似物和CXCR 4激动剂CTCE-0214在三种不同的小鼠全身性炎症模型中具有抗炎作用的假设。我们的研究结果表明，CTCE-0214在体内显著抑制急性内毒素血症和酵母多糖诱导的多器官功能障碍综合征（MODS）后血浆肿瘤坏死因子α（TNF-α）的升高。在两种模型中，CTCE-0214均未抑制血浆中抗炎细胞因子白细胞介素（IL）-10的增加。CTCE-0214改善了盲肠结扎穿孔（CLP）诱导的严重脓毒症模型中无抗生素的生存率。CTCE-0214还降低了响应CLP诱导的炎症的IL-6而非TNF-α和IL-10的血浆升高。我们证明在中度严重的CLP模型（一次穿刺）中，24小时的IL-6水平与假手术对照相似。然而，在重度CLP（两次穿刺）中，血浆IL-6水平显著升高。血浆SDF-1α水平与血浆IL-6呈负相关。除了CTCE-0214在这些体内全身性炎症模型中的有益作用之外，我们还证明了类似物剂量依赖性地抑制LPS诱导的骨髓源性巨噬细胞中的IL-6产生。因此，CTCE-0214可能有益于控制炎症脓毒症和全身性炎症综合征。
The chemokine CXC receptor 4 (CXCR4) is activated by stromal cell-derived factor (SDF-1α). CXCR4 may be part of a lipopolysaccharide (LPS) sensing co-clustering complex that modulates TLR4 activation and evidence suggest that SDF-1α can activate anti-inflammatory signaling pathways and suppress inflammation. In the present study we examined the hypothesis that the SDF-1α peptide analog and CXCR4 agonist CTCE-0214 is anti-inflammatory in three distinct models of murine systemic inflammation. Our findings demonstrate that CTCE-0214 in vivo significantly suppressed plasma tumor necrosis factor alpha (TNF-α) increases in acute endotoxemia and following zymosan-induced multiple organ dysfunction syndrome (MODS). In both models, CTCE-0214 did not suppress plasma increases in the anti-inflammatory cytokine interleukin (IL)-10. CTCE-0214 improved survival without antibiotics in a model of severe sepsis induced by cecal ligation and puncture (CLP). CTCE-0214 also decreased plasma increases in IL-6 but not TNF-α and IL-10 in response to CLP-induced inflammation. We demonstrated in a moderately severe model of CLP (one puncture) that IL-6 levels at 24 h were similar to sham controls. However in severe CLP (two punctures) plasma IL-6 levels were markedly elevated. Plasma SDF-1α levels varied inversely with the plasma IL-6. In addition to the beneficial effect of CTCE-0214 in these models of systemic inflammation in vivo, we also demonstrated that the analog dose dependently suppressed LPS-induced IL-6 production in bone marrow-derived macrophages. CTCE-0214 therefore may be beneficial in controlling inflammation sepsis and systemic inflammatory syndromes.
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DOI：
10.1016/j.bbamcr.2011.01.012
发表时间：
2011-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Fan H;Li P;Zingarelli B;Borg K;Halushka PV;Birnbaumer L;Cook JA
通讯作者：
Cook JA
影响因子：
5
作者：
Lin, Heng-Huei;Chen, Yen-Hui;Chau, Lee-Young
通讯作者：
Chau, Lee-Young
影响因子：
3.1
作者：
Fan, HK;Peck, OM;Cook, JA
通讯作者：
Cook, JA
影响因子：
4.4
作者：
Lentschat, A;Karahashi, H;Arditi, M
通讯作者：
Arditi, M
影响因子：
30.5
作者：
Triantafilou, K;Triantafilou, M;Dedrick, RL
通讯作者：
Dedrick, RL