Lv Qi, Long Manman, Wang Xin, Shi Jie, Wang Pengtao, Guo Xiaoqin, Song Jie, Midgley Adam C, Fan Haojun, Hou Shike
Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China.
Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
Shock. 2021 Dec 1;56(6):1028-1039. doi: 10.1097/SHK.0000000000001839.
Crush syndrome (CS) is the most common cause of deaths following earthquakes and other disasters. The pathogenesis of CS has yet to be fully elucidated. Thus, clinical choice of ideal drug treatments for CS remains deficient.
In this study, we first evaluated the relation between extrusion force and the severities of CS. Rats were exposed to different extrusion forces: 1 kg, 3 kg, 5 kg, and 8 kg, respectively. Survival rates, crushed muscle tissue edema, serum biochemical parameters, and histopathological staining were used to assess severity. Our results showed that there were no statistical differences in survival rate or changes in thigh circumference among the different extrusion forces groups. However, serum levels of potassium, creatine kinase, blood urea nitrogen, creatinine, and myoglobin were elevated at 12- and 24-h post-decompression in 5 kg and 8 kg groups, compared with 1 kg and 3 kg groups. Histopathological staining demonstrated that the degree of organ damage to kidney, muscle, and lung tissues correlated with increasing extrusion force. We next analyzed changes in serum protein profiles in 3 kg or 5 kg extrusion pressure groups. A total of 76 proteins (20 upregulated, 56 downregulated) were found to be altered at all three time points (0, 12, and 72 h) post-decompression, compared with the control group. Three common upregulated proteins alpha-1-acid glycoprotein (α1-AGP), neutrophil gelatinase-associated lipocalin (NGAL), and Haptoglobin were selected for validation of increased expression. α1-AGP was explored as a treatment for CS-induced acute kidney injury (AKI). Intraperitoneal injection of α1-AGP protected kidneys from CS-induced AKI by regulating TNF-α and IL-6 production, attenuating neutrophil recruitment, and reducing renal cell apoptosis.
Our findings demonstrated that the severity of crush injury is causally related to extrusion pressure and increase in blood serum markers. Our identification of the biomarker and treatment candidate, α1-AGP, suggests its implication in predicting the severity of CS and its use as a mediator of CS-induced AKI, respectively.
挤压综合征（CS）是地震和其他灾害后最常见的死亡原因。CS的发病机制尚未完全阐明。因此，CS理想药物治疗的临床选择仍然不足。
在本研究中，我们首先评估了挤压力与CS严重程度之间的关系。将大鼠分别暴露于不同的挤压力：1kg、3kg、5kg和8kg。通过生存率、挤压肌肉组织水肿、血清生化参数和组织病理学染色来评估严重程度。我们的结果表明，不同挤压力组之间的生存率或大腿周长变化没有统计学差异。然而，与1kg和3kg组相比，5kg和8kg组在减压后12小时和24小时时血清钾、肌酸激酶、血尿素氮、肌酐和肌红蛋白水平升高。组织病理学染色表明，肾脏、肌肉和肺组织的器官损伤程度与挤压力增加相关。接下来，我们分析了3kg或5kg挤压压力组血清蛋白质谱的变化。与对照组相比，在减压后的所有三个时间点（0、12和72小时）共发现76种蛋白质（20种上调，56种下调）发生改变。选择三种常见的上调蛋白质α1-酸性糖蛋白（α1-AGP）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和触珠蛋白进行表达增加的验证。探索了α1-AGP作为CS诱导的急性肾损伤（AKI）的治疗方法。腹腔注射α1-AGP通过调节TNF-α和IL-6的产生、减少中性粒细胞募集和减少肾细胞凋亡来保护肾脏免受CS诱导的AKI。
我们的研究结果表明，挤压伤的严重程度与挤压力和血清标志物的增加有因果关系。我们对生物标志物和治疗候选物α1-AGP的确立，分别表明了其在预测CS严重程度和作为CS诱导的AKI介质方面的意义。
