Department of Bioengineering, University of California, San Diego, USA.
Transfusion. 2013 Feb;53(2):424-37. doi: 10.1111/j.1537-2995.2012.03774.x. Epub 2012 Jul 15.
Cell-free hemoglobin (Hb) has been blamed for a spectrum of problems, including vasoconstriction pancreatitis, myocardial infarction, and pulmonary hypertension in hemolytic anemia, malaria, and sickle cell anemia, and from Hb-based oxygen carriers (HBOCs). Toxicities have been attributed to scavenging of nitric oxide (NO). However, while NO scavenging may explain many in vitro effects, and some effects in animal models and clinical trials with HBOCs, key inconsistencies in the theory require alternative explanations. This review considers the hypothesis that cell-free Hb oversupplies oxygen to tissues, leading to oxygen-related toxicity, possibly through formation of reactive oxygen species and local destruction of NO. Evidence for this hypothesis comes from various sources, establishing that tissue oxygen levels are maintained over very narrow (and low) levels, even at high oxygen consumption. Tissue is normally protected from excessive oxygen by its extremely low solubility in plasma, but introduction of cell-free Hb, even at low concentration, greatly augments oxygen supply, engaging protective mechanisms that include vasoconstriction and ischemia. The requirement to limit oxygen supply by cell-free Hb suggests novel ways to modify it to overcome vasoconstriction, independent of the intrinsic reaction of Hb with NO. This control is essential to the design of a safe and effective cell-free HBOC.
无细胞血红蛋白 (Hb) 被归咎于一系列问题，包括溶血性贫血、疟疾和镰状细胞贫血中的血管收缩性胰腺炎、心肌梗死和肺动脉高压，以及血红蛋白基氧载体 (HBOC) 也是如此。毒性归因于一氧化氮 (NO) 的清除。然而，虽然 NO 清除可能解释了许多体外效应，以及 HBOC 动物模型和临床试验中的一些效应，但该理论中的关键不一致性需要其他解释。这篇综述考虑了这样一种假设，即无细胞 Hb 过度供应组织氧气，导致与氧气相关的毒性，可能是通过形成活性氧和局部破坏 NO 引起的。这一假设的证据来自各种来源，证明组织氧水平在非常狭窄（且较低）的水平下得到维持，即使在高耗氧量下也是如此。组织通常通过其在血浆中的极低溶解度来防止过度氧气，但即使引入低浓度的无细胞 Hb，也会大大增加氧气供应，引发包括血管收缩和缺血在内的保护机制。无细胞 Hb 限制氧气供应的要求表明了一种修饰它以克服血管收缩的新方法，而不依赖于 Hb 与 NO 的内在反应。这种控制对于设计安全有效的无细胞 HBOC 至关重要。
