Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Sci Rep. 2020 Oct 15;10(1):17413. doi: 10.1038/s41598-020-74529-4.
Recombinant thrombomodulin (rTM) has been used for treatment of sepsis-associated disseminated intravascular coagulation. Recent studies have suggested that anticoagulant therapy might dampen the protective role of immunothrombosis. We examined if rTM might worsen infectious diseases. Male Sprague-Dawley rats with jugular-vein catheterization were divided into three groups: no anticoagulation; rTM pretreatment; rTM treatment at 6 h. Live methicillin-resistant Staphylococcus aureus (MRSA) was inoculated into the tail vein of rats. rTM was administered into the jugular-vein catheter before or 6 h after MRSA inoculation, while an equal volume of saline was administered in the no-anticoagulation group. Blood samples were collected from the jugular-vein catheter before, 6 h and 12 h after MRSA inoculation. Tissue samples were collected from anesthetized rats when moribund or 18 h after MRSA inoculation. The survival rate of rats in the no-anticoagulation group, rTM pretreatment group, and rTM treatment at 6-h group was 50%, 25%, and 75%, respectively. Bacterial burden in blood, lung, liver, and spleen was neither increased nor decreased in rats treated with rTM. The ratio of bacteria found in the extravascular space to those in the intravascular space was increased in rats treated with rTM although the statistical power for this was low because of the small sample size. Metabolomics analysis revealed that rTM treatment alleviated oxidative stress, as evidenced by the decrease in levels of oxidized glutathione with reference to reduced glutathione. rTM did not promote bacterial propagation but alleviated oxidative stress in our rat model of bloodstream infection with MRSA. Further large-scale studies are needed to confirm these findings.
重组血栓调节蛋白（rTM）已被用于治疗脓毒症相关弥散性血管内凝血。最近的研究表明，抗凝治疗可能会削弱免疫血栓形成的保护作用。我们研究了 rTM 是否会加重感染性疾病。颈静脉置管的雄性 Sprague-Dawley 大鼠分为三组：不抗凝；rTM 预处理；rTM 在 6 小时时治疗。将活耐甲氧西林金黄色葡萄球菌（MRSA）接种到大鼠尾静脉。rTM 在 MRSA 接种前或接种后 6 小时经颈静脉导管给药，而在无抗凝组中给予等量的生理盐水。在 MRSA 接种前、6 小时和 12 小时从颈静脉导管采集血样。在 MRSA 接种后濒死或 18 小时时从麻醉大鼠采集组织样本。无抗凝组、rTM 预处理组和 rTM 在 6 小时时治疗组大鼠的存活率分别为 50%、25%和 75%。rTM 治疗组大鼠的血液、肺、肝和脾中的细菌负荷既未增加也未减少。尽管由于样本量小，统计效能较低，但 rTM 治疗组大鼠血管外空间中的细菌与血管内空间中的细菌比值增加。代谢组学分析表明，rTM 治疗减轻了氧化应激，这表现在氧化型谷胱甘肽相对于还原型谷胱甘肽的水平降低。rTM 没有促进细菌繁殖，但在我们的耐甲氧西林金黄色葡萄球菌血流感染大鼠模型中减轻了氧化应激。需要进一步的大规模研究来证实这些发现。
