Zhang Fangming, Yang Weng-Lang, Brenner Max, Wang Ping
From the Center for Immunology and Inflammation (F.Z., W.-L.Y., M.B., P.W.), The Feinstein Institute for Medical Research; and Department of Surgery (W-L.Y., P.W.), Hofstra Northwell School of Medicine, Manhasset, NY.
J Trauma Acute Care Surg. 2017 Oct;83(4):690-697. doi: 10.1097/TA.0000000000001566.
Hemorrhagic shock (HS) is an important cause of mortality. HS is associated with an elevated incidence of acute lung injury and acute respiratory distress syndrome, significantly contributing to HS morbidity and mortality. Cold-inducible RNA-binding protein (CIRP) is released into the circulation during HS and can cause lung injury. C23 is a CIRP-derived oligopeptide that binds with high affinity to the CIRP receptor and inhibits CIRP-induced phagocyte secretion of TNF-α. This study was designed to determine whether C23 is able to attenuate HS-associated lung injury.
C57BL/6 mice were subjected to controlled hemorrhage leading to a mean arterial pressure of 25 ± 3 mm Hg for 90 minutes. Mice were then volume-resuscitated for 30 minutes with normal saline solution alone (vehicle) or plus adjuvant treatment with C23 (8 mg/kg BW). At 4.5 hours after resuscitation, the blood and lungs were harvested.
Serum levels of organ injury markers lactate dehydrogenase, aspartate aminotransferase were significantly elevated in hemorrhaged mice receiving vehicle and were reduced by 51.3% and 52.2% in mice adjuvantly treated with C23, respectively. Similarly, lung mRNA levels of IL-1β, TNF-α, and IL-6, and lung myeloperoxidase activity were elevated after HS and reduced by 66.1%, 54.4%, 69.7%, and 24.3%, respectively, in mice treated with C23. Adjuvant treatment with C23 also decreased the lung histology score by 33.9%, lung extravasation of albumin carrying Evans blue dye by 36.8%, and the protein level of intercellular adhesion molecule-1, and indicator of vascular endothelial cell activation, by 40.3%.
Together, these results indicate that adjuvant treatment with the CIRP-derived oligopeptide C23 is able to improve lung inflammation and vascular endothelial activation secondary to HS, lending support to the development of CIRP-targeting adjuvant treatments to minimize lung injury after HS.
失血性休克（HS）是导致死亡的重要原因。HS与急性肺损伤和急性呼吸窘迫综合征的发病率升高相关，这显著增加了HS的发病率和死亡率。冷诱导RNA结合蛋白（CIRP）在HS期间释放到循环中，并可导致肺损伤。C23是一种源自CIRP的寡肽，它与CIRP受体具有高亲和力结合，并抑制CIRP诱导的吞噬细胞分泌肿瘤坏死因子-α（TNF-α）。本研究旨在确定C23是否能够减轻HS相关的肺损伤。
将C57BL/6小鼠进行控制性出血，使平均动脉压维持在25±3 mmHg，持续90分钟。然后，小鼠单独用生理盐水（载体）或加用C23（8 mg/kg体重）辅助治疗进行30分钟的容量复苏。复苏后4.5小时，采集血液和肺组织。
接受载体治疗的出血小鼠血清中器官损伤标志物乳酸脱氢酶、天冬氨酸转氨酶水平显著升高，而接受C23辅助治疗的小鼠分别降低了51.3%和52.2%。同样，HS后肺组织中白细胞介素-1β（IL-1β）、TNF-α和IL-6的mRNA水平以及肺髓过氧化物酶活性升高，而在接受C23治疗的小鼠中分别降低了66.1%、54.4%、69.7%和24.3%。C23辅助治疗还使肺组织学评分降低了33.9%，携带伊文思蓝染料的白蛋白肺外渗减少了36.8%，细胞间黏附分子-1（血管内皮细胞活化指标）的蛋白水平降低了40.3%。
总之，这些结果表明，用源自CIRP的寡肽C23进行辅助治疗能够改善HS继发的肺部炎症和血管内皮细胞活化，为开发以CIRP为靶点的辅助治疗方法以尽量减少HS后的肺损伤提供了支持。
