Cell-free oxygen carriers: scientific foundations, clinical development, and new directions.
Cell-free oxygen carriers: scientific foundations, clinical development, and new directions.
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DOI：
10.1016/j.bbapap.2008.04.032
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
R. Winslow
中科院分区：
文献类型：
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作者：
R. Winslow
开发安全有效的基于血红蛋白的氧载体（“血液替代品”）的最重要障碍通常被认为是其在微循环中引起血管收缩和高血压的倾向。目前正在研究这种效应的两种理论：一种是通过血红蛋白清除NO减少血管舒张;另一种是无细胞血红蛋白通过促进扩散向血管壁过度供应O2（一种已知的血管收缩剂）。虽然这两种机制都可能导致局部NO浓度的降低，但两者之间的重要区别在于，如果NO清除理论是正确的，则它极大地减少了开发基于游离血红蛋白的任何解决方案的前景。然而，如果O2-过量供应理论是正确的，那么可以设想对血红蛋白分子进行修饰，以防止过量供应并降低毒性。这篇综述总结了Hemospan®的发展，Hemospan ®是一种新型的人血红蛋白修饰物，其设计基于O2-供过于求理论。由于其低P50和增加的分子大小，Hemospan在阻力血管（小动脉）中的O2释放受到限制，血管收缩大大减少。
The most significant hurdle to the development of a safe and effective hemoglobin-based oxygen carrier (“blood substitute”) is generally thought to be its propensity to cause vasoconstriction in the microcirculation and hypertension. Two theories for this effect are currently being studied: in one, scavenging NO by hemoglobin reduces vasorelaxation; in the other, cell-free hemoglobin oversupplies O2(a known vasoconstrictor) to vascular walls by facilitated diffusion. While both mechanisms might lead to reduction of local NO concentration, the important distinction between the two is that if the NO scavenging theory is correct, it greatly diminishes the prospects to develop any solution based on free hemoglobin. However, if the O2-oversupply theory is correct, modifications to the hemoglobin molecule can be envisioned that can prevent oversupply and reduce toxicity. This review summarizes the development of Hemospan®, a novel modification of human hemoglobin whose design is based on the O2-oversupply theory. Because of its low P50 and increased molecular size, the release of O2in resistance vessels (arterioles) by Hemospan is restricted, and vasoconstriction is greatly reduced.