Pegylated hemoglobins mechanisms to avoid vasoconstriction and maintain perfusion

P. Cabrales, J. Friedman
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引用次数: 15

Abstract

SUMMARY Despite the advances in blood substitutes, the development of materials that are effective in maintaining blood volume and oxygen delivery remains the priority for emergency care and trauma. Vasoactivity, i.e. vasoconstriction, presumably caused by nitric oxide (NO) scavenging has been defined as the principal problem associated with acellular hemoglobin (Hb) with low hydrodynamic radius. Conversely, Hb-based materials with very large hydrodynamic radius, achieved by surface decoration of the Hb tetramer with water-trapping polymers such as polyethylene glycol (PEG) conjugation, have been found vasoinactive in spite of being effective NO scavengers. This article explores possible mechanisms for why PEGylated Hbs not only are not vasoconstrictive but also are actually facilitators for maintaining high perfusion levels in the microcirculation. The most promising mechanisms are based on relatively recent observations and models; they indicate that Hb can actively regulate availability of ‘bioactive’ NO forms. This regulation can occur via: (i) NO transport by Hb in an allosterically controlled reversible chemical reaction with the Cys beta 93 (S-NO-Hb); and (ii) production of bioactive forms of NO through nitrite reductase activity of deoxyHb. The principal issues associated with these proposed mechanisms are: (i) how these reactions generate bio-available NO and (ii) how the generated NO is delivered to the site of action without being either degraded or sequestered. We present a promising hypothesis and preliminary supporting data that PEGylated Hbs through a nitrite-mediated reaction are especially effective in generating nitrosothiols, creating a transportable source of bioactive NO.
聚乙二醇化血红蛋白避免血管收缩和维持灌注的机制
尽管血液替代品取得了进步,但开发有效维持血容量和氧气输送的材料仍然是急诊护理和创伤的优先事项。血管活性,即血管收缩,可能是由一氧化氮(NO)清除引起的,已被定义为与低流体动力半径的脱细胞血红蛋白(Hb)相关的主要问题。相反,通过用聚乙二醇(PEG)偶联等捕水聚合物对Hb四聚体进行表面修饰而获得的具有非常大流体动力学半径的Hb基材料,尽管是有效的NO清除剂,但却具有血管无活性。本文探讨了为什么聚乙二醇化Hbs不仅不收缩血管,而且实际上是维持微循环高灌注水平的促进剂的可能机制。最有希望的机制是基于相对较新的观测和模型;他们表明Hb可以积极调节“生物活性”NO形式的可用性。这种调节可以通过以下途径发生:(i) Hb通过与Cys β 93 (S-NO-Hb)发生变构控制的可逆化学反应转运NO;(ii)通过脱氧血红蛋白的亚硝酸盐还原酶活性产生生物活性形式的NO。与这些提议的机制相关的主要问题是:(i)这些反应如何产生生物可利用的NO和(ii)产生的NO如何被递送到作用部位而不被降解或隔离。我们提出了一个有希望的假设和初步的支持数据,即通过亚硝酸盐介导的反应聚乙二醇化Hbs在生成亚硝基硫醇方面特别有效,创造了一种可运输的生物活性NO来源。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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