Department of Bioengineering, University of California, San Diego, CA, USA.
Antioxid Redox Signal. 2013 Jun 10;18(17):2284-97. doi: 10.1089/ars.2012.5099. Epub 2013 Feb 12.
Despite many advances in blood substitute research, the development of materials that are effective in maintaining blood volume and oxygen delivery remains a priority for emergency care and trauma. Clinical trials on hemoglobin (Hb)-based oxygen carriers (HBOCs) have not provided information on the mechanism of toxicity, although all commercial formulations have safety concerns. Specifically, it is important to reconcile the different hypotheses of Hb toxicity, such as nitric oxide (NO) depletion and oxidative reactions, to provide a coherent molecular basis for designing a safe HBOC.
HBOCs with different sizes often exhibit differences in the degree of HBOC-induced vasoactivity. This has been attributed to differences in the degree of NO scavenging and in the extent of Hb extravasation. Additionally, it is appears that Hb can undergo reactions that compensate for NO scavenging by generating bioactive forms of NO.
Engineering modifications to enhance bioactive NO production can result in diminished oxygen delivery by virtue of increased oxygen affinity. This strategy can prevent the HBOC from fulfilling the intended goal on preserving oxygenation; however, the NO production effects will increase perfusion and oxygen transport.
Hb modifications influence NO scavenging and the capacity of certain HBOCs to compensate for NO scavenging through nitrite-mediated reactions that generate bioactive NO. Based on the current understanding of these NO-related factors, possible synthetic strategies are presented that address how HBOC formulations can be prepared that: (i) effectively deliver oxygen, (ii) maintain tissue perfusion, and (iii) limit/reverse underlying inflammation within the vasculature.
尽管血液代用品的研究已经取得了许多进展，但开发出能够有效维持血容量和输送氧气的材料仍然是急救和创伤治疗的优先事项。基于血红蛋白（Hb）的氧载体（HBOC）的临床试验并未提供关于毒性机制的信息，尽管所有商业制剂都存在安全问题。具体来说，重要的是要调和 Hb 毒性的不同假说，如一氧化氮（NO）耗竭和氧化反应，为设计安全的 HBOC 提供一个连贯的分子基础。
具有不同大小的 HBOC 通常在 HBOC 诱导的血管活性程度上表现出差异。这归因于 NO 清除和 Hb 渗出程度的差异。此外，Hb 似乎可以发生反应，通过生成生物活性形式的 NO 来补偿 NO 的清除。
工程修饰以增强生物活性 NO 的产生会导致由于氧亲和力增加而导致氧输送减少。这种策略可以防止 HBOC 实现保持氧合的预期目标；然而，NO 产生的效果将增加灌注和氧气输送。
Hb 的修饰会影响 NO 的清除以及某些 HBOC 通过亚硝酸盐介导的反应来补偿 NO 清除的能力，从而产生生物活性的 NO。基于对这些与 NO 相关因素的现有理解，提出了可能的合成策略，这些策略涉及如何制备 HBOC 制剂：（i）有效地输送氧气，（ii）维持组织灌注，以及（iii）限制/逆转血管内的潜在炎症。
