van Leeuwen Anoek L I, Dekker Nicole A M, Van Slyke Paul, de Groot Esther, Vervloet Marc G, Roelofs Joris J T H, van Meurs Matijs, van den Brom Charissa E
Department of Anesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.
Intensive Care Med Exp. 2021 May 17;9(1):23. doi: 10.1186/s40635-021-00389-5.
Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function.
Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis.
Hemorrhagic shock significantly decreased renal perfusion (240 ± 138 to 51 ± 40, p < 0.0001) and cremaster perfusion (12 ± 2 to 5 ± 2 perfused vessels, p < 0.0001) compared to baseline values. Fluid resuscitation partially restored both perfusion parameters, but both remained below baseline values (renal perfusion 120 ± 58, p = 0.08, cremaster perfusion 7 ± 2 perfused vessels, p < 0.0001 compared to baseline). Hemorrhagic shock increased circulating angiopoietin-1 (p < 0.0001), angiopoietin-2 (p < 0.0001) and soluble Tie2 (p = 0.05), of which angiopoietin-2 elevation was associated with renal edema formation (r = 0.81, p < 0.0001). Hemorrhagic shock induced renal injury, as assessed by increased levels of plasma neutrophil gelatinase-associated lipocalin (NGAL: p < 0.05), kidney injury marker-1 (KIM-1; p < 0.01) and creatinine (p < 0.05). Vasculotide did not improve renal perfusion (p > 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 ± 3 vs 8 ± 3 perfused vessels, p < 0.05).
Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy.
失血性休克与急性肾损伤及死亡率增加相关。靶向调节内皮通透性的内皮血管生成素/Tie2系统，此前已减少失血性休克诱导的血管渗漏。我们推测，由于血管渗漏，肾灌注和功能受损，激活Tie2可恢复肾灌注和功能。
对大鼠进行1小时失血性休克，随后分别用血管肽或磷酸盐缓冲液（PBS）作为对照进行治疗，接着进行4小时的液体复苏。分别使用超声造影和活体显微镜在肾皮质和提睾肌中测量微循环灌注。在血浆以及肾组织的蛋白质和mRNA水平上测量血管生成素/Tie2系统和肾损伤标志物的变化。通过湿/干重比确定肾水肿形成情况，并通过组织学分析确定肾脏结构。
与基线值相比，失血性休克显著降低了肾灌注（从240±138降至51±40，p<0.0001）和提睾肌灌注（从12±2降至5±2条灌注血管，p<0.0001）。液体复苏部分恢复了两个灌注参数，但两者仍低于基线值（肾灌注120±58，p = 0.08；提睾肌灌注7±2条灌注血管，与基线相比p<0.0001）。失血性休克增加了循环血管生成素-1（p<0.0001）、血管生成素-2（p<0.0001）和可溶性Tie2（p = 0.05），其中血管生成素-2升高与肾水肿形成相关（r = 0.81，p<0.0001）。失血性休克诱导了肾损伤，这通过血浆中性粒细胞明胶酶相关脂质运载蛋白（NGAL：p<0.05）、肾损伤标志物-1（KIM-1；p<0.01）和肌酐（p<0.05）水平的升高来评估。血管肽并未改善肾灌注（所有时间点p>0.9）或减轻肾损伤（NGAL p = 0.26，KIM-1 p = 0.78，肌酐p>0.9，肾水肿p = 0.08），但与未治疗的大鼠相比，在液体复苏开始后3小时暂时改善了提睾肌灌注（复苏+3小时：11±3对8±3条灌注血管，p<0.05）。
标准液体复苏或激活Tie2均无法恢复失血性休克诱导的肾功能损害。未来的治疗策略应侧重于降低血管生成素-2水平或通过替代策略激活Tie2。
