The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.
The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.
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DOI：
10.1097/cce.0000000000000701
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发表时间：
2022-05
影响因子：
--
通讯作者：
Majetschak, Matthias
中科院分区：
文献类型：
--
作者：
DeSantis, Anthony J.;Weche, Mcwayne;Enten, Garrett A.;Gao, Xianlong;Majetschak, Matthias
临床相关性提示，在创伤失血性休克早期炎症反应中，全身趋化因子(C-C基序)配体(CCL)2的释放可能参与了血压调节和血流动力学不稳定的发展。因此，我们研究了阻断主要的CCL2受体趋化因子(C-C基序)受体(CCR)2是否影响正常动物的血压，以及失血性休克模型中血流动力学和复苏液体的需求。随机前瞻性治疗研究。大学实验室。雄性SD大鼠。首先，用剂量递增的INCB3284或赋形剂治疗健康麻醉大鼠。然后用CCR2拮抗剂INCB32 84(1.1和5.5μμ/kg)、CCR5拮抗剂马拉韦罗(=对照组，5.5μmol/kg)或赋形剂处理大鼠30分钟，然后进行液体复苏以维持血压，直到t=90 min。失血复苏后给予5Mol/kgINCB3284或赋形剂治疗，直至t=300min。在压力肌图实验中，INCB3284不影响分离的大鼠阻力动脉的固有功能。麻醉剂处理的动物血压持续下降0.09 ± 0.01 mm Hg/min(p<；0.001)，但注射INCB3284后血压保持不变。CCR2激动剂CCL2、CCL5和CCL11的全身浓度在出血和液体复苏期间升高。在短期实验中，INCB3284剂量依赖性地将液体需求量减少了58%±11%，而马拉韦罗和赋形剂治疗的动物没有区别。当复苏到t=300分钟时，INCB3284减少了62%±6%的液体需求，防止了血流动力学失代偿，将死亡率从使用赋形剂治疗的50%降至零，并降低了总体组织湿/干重比。我们的研究结果表明，CCR2参与了正常心血管功能的调节以及失血性休克和液体复苏后的心血管应激反应。本研究确定CCR2是一种药物靶点，用于减少失血性休克复苏过程中的液体需求和防止血流动力学失代偿死亡。
Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models. Randomized prospective treatment study. University laboratory. Male Sprague-Dawley rats. First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 μmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 μmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until t = 90 minutes. Third, treatment of rats with 5 μmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until t = 300 minutes. INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min (p < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until t = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios. Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock.
DOI：
10.1016/j.bbrc.2009.10.067
发表时间：
2009-12-25
影响因子：
3.1
作者：
Geng, Qing;Romero, Jacqueline;Saini, Vikas;Baker, Todd A.;Picken, Maria M.;Gamelli, Richard L.;Majetschak, Matthias
通讯作者：
Majetschak, Matthias
DOI：
10.1016/j.jss.2011.12.015
发表时间：
2012-11
期刊：
The Journal of surgical research
影响因子：
--
作者：
Gómez H;Mesquida J;Hermus L;Polanco P;Kim HK;Zenker S;Torres A;Namas R;Vodovotz Y;Clermont G;Puyana JC;Pinsky MR
通讯作者：
Pinsky MR