Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Thorac Cardiovasc Surg. 2017 Dec;154(6):1973-1983.e1. doi: 10.1016/j.jtcvs.2017.05.051. Epub 2017 May 30.
Cardiopulmonary bypass (CPB) may induce systemic inflammatory responses causing acute lung injury. Recombinant human soluble thrombomodulin (rTM) is reported to attenuate the secretion of inflammatory cytokines and the high-mobility group box 1 (HMGB1) protein, which is critical in controlling systemic inflammation and apoptosis. We investigated the protective effects of rTM on CPB-induced lung injury in a rat model.
Eighteen male Sprague-Dawley rats were divided into 3 groups: sham, control (CPB alone), and rTM (CPB + rTM). CPB was conducted in the control group and the rTM group. A bolus of rTM (3 mg/kg) was administered to the rTM group rats before CPB establishment.
The ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen only dropped markedly from before CPB in the control group (P < .001). Serum tumor necrosis factor α, interleukin (IL) 6, and HMGB1 levels were significantly higher in the control group after CPB. Pathologic study revealed significantly more severe congestion, alveolar hemorrhage, neutrophil accumulation, and edema, and the number of lung cells expressing HMGB1 increased in the control group. The mRNA expression levels of tumor necrosis factor α, IL-6, IL-1β, and HMGB1 in the control group were significantly higher than those in other groups. According to Western blot analysis, nuclear factor-κB p65 in lung tissue was significantly downregulated in the rTM group. The number of apoptotic cells and the protein of cleaved Caspase-3 were reduced in the rTM group.
These results suggest that rTM prevents acute lung injury through attenuating inflammation and apoptosis during and after CPB in a rat model.
体外循环（CPB）可能会引起全身炎症反应，导致急性肺损伤。重组人可溶性血栓调节蛋白（rTM）可减轻炎症细胞因子和高迁移率族蛋白 1（HMGB1）的分泌，这对于控制全身炎症和细胞凋亡至关重要。我们在大鼠模型中研究了 rTM 对 CPB 诱导的肺损伤的保护作用。
将 18 只雄性 Sprague-Dawley 大鼠随机分为 3 组：假手术组、对照组（仅 CPB）和 rTM 组（CPB+rTM）。在对照组和 rTM 组进行 CPB。在建立 CPB 前，rTM 组大鼠给予 rTM（3mg/kg）推注。
对照组 CPB 后动脉血氧分压与吸入氧分数之比仅明显下降（P<0.001）。CPB 后对照组血清肿瘤坏死因子-α、白细胞介素（IL）6 和 HMGB1 水平明显升高。病理研究显示，对照组充血、肺泡出血、中性粒细胞积聚和水肿更为严重，HMGB1 表达的肺细胞数量增加。对照组肿瘤坏死因子-α、IL-6、IL-1β和 HMGB1 的 mRNA 表达水平明显高于其他组。根据 Western blot 分析，rTM 组肺组织核因子-κB p65 明显下调。rTM 组凋亡细胞数和 cleaved Caspase-3 蛋白减少。
这些结果表明，rTM 通过减轻 CPB 期间和之后的炎症和细胞凋亡，在大鼠模型中预防急性肺损伤。
