Vasoactive, pro-inflammatory and pro-coagulant effects of hemoglobin-based oxygen carriers in a murine model of hemorrhagic shock

2007年在德国，道路交通事故夺去了近5 000人的生命，并给43万多人造成了危及生命的创伤。这些人中的许多人有出血性休克，需要液体复苏。与透明液体相比，无细胞血红蛋白氧载体（HBOC）携带氧气，并在无法获得血型匹配血液时为失血性休克患者的器官提供有效的代谢支持。多年来一直在追求HBOC的安全有效使用这一目标，但没有成功，最近是由于接受HBOC的患者发生过多的心肌梗死和死亡。许多人认为这种有害的副作用是由于HBOC清除NO。在本项目中，我们将重点研究HBOCs的血管活性、促炎性和促凝性副作用，以及通过吸入NO补充预防这些副作用。具体而言，我们将（i）表征和比较HBOC、四聚血红蛋白和全血在野生型小鼠和先天性内皮NO合酶（NOS 3-/-）缺陷小鼠中的促炎和促凝作用，（ii）测试呼吸NO是否可以预防这些有害的HBOC诱导的副作用，和（iii）研究吸入NO和HBOC输注的组合对血液动力学和生化反应，以及关键器官组织氧合的功效，细胞死亡和炎症在一个良好的表征鼠出血性休克模型。通过这种方式，我们希望在血液不可用的情况下开辟一条安全有效地使用HBOCs的途径，同时防止有害的副作用。

In Germany in 2007, road accidents claimed nearly 5,000 lives and caused life-threatening trauma to more than 430,000 people. Many of these individuals had hemorrhagic shock and required fluid resuscitation. As compared to clear fluids, cell-free hemoglobin-based oxygen carriers (HBOC) carry oxygen and could provide effective metabolic support for the organs of the injured patient with hemorrhagic shock when typematched blood is unavailable. This goal of a safe and effective use of HBOC has been pursued for years without success, most recently due to an excess of myocardial infarction and death in patients receiving HBOCs. Many believe that this noxious side-effect is due to NO scavenging by HBOC. In the present project, we will focus on studying the vasoactive, pro-inflammatory, and pro-coagulant side effects of HBOCs and their prevention by inhaled NO supplementation. Specifically, we will (i) characterize and compare the proinflammatory and pro-coagulant effects of HBOC, tetrameric hemoglobin, and whole blood in both wild-type mice and mice congenitally deficient in endothelial NO synthase (NOS3-/-), (ii) test whether breathing NO can prevent these noxious HBOC-induced side effects, and (iii) investigate the efficacy of the combination of inhaled NO and HBOC infusion on hemodynamic and biochemical responses, as well as key organ tissue oxygenation, cell death and inflammation in a well-characterized murine hemorrhagic shock model. In this manner we hope to open a pathway to the safe and effective use of HBOCs when blood is unavailable, while preventing noxious side-effects.