A novel CCR5/CXCR3 antagonist protects intestinal ischemia/reperfusion injury
A novel CCR5/CXCR3 antagonist protects intestinal ischemia/reperfusion injury
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DOI：
10.1016/j.transproceed.2006.10.115
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发表时间：
2006-12-01
影响因子：
0.9
通讯作者：
Nakajima, Y.
中科院分区：
文献类型：
--
作者：
Akahori, T.;Sho, M.;Nakajima, Y.
趋化因子和趋化因子受体已被证明是多种生理和病理免疫反应的关键调节剂。特别是，CCR 5和CXCR 3已被报道在同种免疫应答中发挥重要作用。在这项研究中，我们研究了一种新的小分子化合物，TAK 779，一种靶向CCR 5和CXCR 3的拮抗剂在肠缺血/再灌注（I/R）损伤中的治疗效果。我们利用一个建立的小鼠肠I/R损伤模型。TAK 779治疗显著改善了肠缺血60分钟后的小鼠存活率。然后，我们使用实时PCR检测了再灌注后2小时几种细胞因子和趋化因子的局部肠表达。TAK 779治疗下调了几种细胞因子的表达，包括TNF-α、IFN-γ和IL-4，表明TAK 779的有益作用与抑制局部免疫激活有关。我们进一步检查了TAK 779治疗后的全身反应。通过肠I/R损伤后4小时的肺湿干重比测定，治疗显著预防了肺组织损伤。此外，我们观察到，肺中的CCR 5表达通过治疗显著下调，表明TAK 779抑制了CCR 5阳性细胞向远端器官的浸润。我们的数据表明CCR 5和CXCR 3在肠I/R损伤中的关键作用以及新型小分子化合物TAK 779对肠I/R损伤的保护作用。
Chemokines and chemokine receptors have been demonstrated to be critical regulators in a variety of physiologic and pathologic immune responses. In particular, CCR5 and CXCR3 have been reported to play important roles in the alloimmune response. In this study, we investigated the therapeutic efficacy of a novel small-molecule compound, TAK779, an antagonist targeting both CCR5 and CXCR3 in intestinal ischemia/reperfusion (I/R) injury. We utilized an established murine intestinal I/R injury model. TAK779 treatment significantly improved mouse survival after 60 minutes of intestinal ischemia. We then examined the local intestinal expression of several cytokines and chemokines at 2 hours after reperfusion using real-time PCR. TAK779 treatment downregulated the expression of several cytokines, including TNF-alpha, IFN-gamma, and IL-4, suggesting that the beneficial effect of TAK779 was associated with inhibition of local immune activation. We further examined the systemic response after TAK779 treatment. Lung tissue damage was significantly prevented by the treatment, as determined by lung wet-to-dry weight ratios at 4 hours after intestinal I/R injury. In addition, we observed that CCR5 expression in the lung was significantly downregulated by the treatment, suggesting that TAK779 inhibited the infiltration of CCR5-positive cells into the remote organ. Our data suggest the critical role of CCR5 and CXCR3 in intestinal I/R injury and therapeutic efficacy of a novel small compound, TAK779, for protection against the intestinal I/R injury.