Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Blood Transfus. 2021 Sep;19(5):420-427. doi: 10.2450/2021.0361-20. Epub 2021 Jan 27.
The benefits of plasma as an adjunct to the treatment of haemorrhagic shock are well established; however, the mechanism by which plasma modulates the endotheliopathy of trauma remains unclear. Our recent data demonstrated a novel role of microRNA-19b in post-haemorrhagic shock endothelial dysfunction via targeting of syndecan-1. Additionally, fibrinogen, as a key component of plasma or an isolated haemostatic protein, protects the endothelium by stabilizing syndecan-1. We therefore hypothesized that fibrinogen would inhibit microRNA-19b to mitigate the endotheliopathy of trauma in a murine model of haemorrhagic shock.
C57BL/6J mice were subjected to haemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 minutes) followed by resuscitation with lactated Ringer's, fresh frozen plasma, fibrinogen or no resuscitation. MicroRNA-19b and syndecan-1 mRNA were measured in lung tissue by qRT-PCR. Lungs were stained for histopathologic injury, and broncheoalveolar lavage was collected for protein as a permeability indicator.
Pulmonary microRNA-19b was increased after haemorrhagic shock and lactated Ringers, but reduced to sham levels by plasma and fibrinogen. Conversely, pulmonary syndecan-1 mRNA was downregulated by haemorrhagic shock and lactated Ringers, but returned to sham levels by plasma and fibrinogen. Plasma and fibrinogen-based resuscitation reduced lung injury compared to haemorrhagic shock and lactated Ringers while fibrinogen also reduced broncheoalveolar lavage protein.
We have demonstrated a novel mechanism by which fibrinogen, a key component of plasma and haemostatic agent, inhibits miR-19b, possibly by mitigating the endotheliopathy of trauma. Complete demonstration of the mechanism of fibrinogen inhibition of endotheliopathy via microRNA, however, remains to be elucidated. These findings support the early and empiric use of fibrinogen in post-haemorrhagic shock resuscitation.
已有充分证据表明，血浆作为治疗失血性休克的辅助手段具有诸多益处；然而，血浆调节创伤内皮病变的机制尚不清楚。我们最近的数据表明，miR-19b 通过靶向连接蛋白-1（syndecan-1），在失血性休克后内皮功能障碍中发挥了一种新的作用。此外，纤维蛋白原作为血浆或孤立止血蛋白的关键成分，通过稳定连接蛋白-1 来保护内皮。因此，我们假设纤维蛋白原将通过抑制 microRNA-19b 来减轻失血性休克后内皮病变，在失血性休克的小鼠模型中验证该假说。
C57BL/6J 小鼠经历失血性休克（平均动脉压 35±5mmHg 持续 90 分钟），随后用乳酸林格氏液、新鲜冷冻血浆、纤维蛋白原或不复苏进行复苏。通过 qRT-PCR 测量肺组织中的 microRNA-19b 和 syndecan-1 mRNA。对肺组织进行组织病理学损伤染色，并收集支气管肺泡灌洗液作为通透性指标。
失血性休克和乳酸林格氏液后，肺部 microRNA-19b 增加，但血浆和纤维蛋白原将其降低至假手术水平。相反，失血性休克和乳酸林格氏液后，肺组织 syndecan-1 mRNA 下调，但血浆和纤维蛋白原将其恢复至假手术水平。与失血性休克和乳酸林格氏液相比，血浆和纤维蛋白原复苏降低了肺损伤，而纤维蛋白原还降低了支气管肺泡灌洗液蛋白。
我们已经证明了纤维蛋白原作为血浆和止血剂的关键成分，通过抑制 miR-19b 抑制内皮病变的新机制，可能通过减轻创伤内皮病变。然而，纤维蛋白原通过 microRNA 抑制内皮病变的机制仍有待阐明。这些发现支持在失血性休克复苏中早期和经验性地使用纤维蛋白原。
