Williams Alexander T, Lucas Alfredo, Muller Cynthia R, Bolden-Rush Crystal, Palmer Andre F, Cabrales Pedro
Department of Bioengineering, University of California, San Diego, La Jolla, California.
William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio.
J Appl Physiol (1985). 2020 Jul 1;129(1):97-107. doi: 10.1152/japplphysiol.00016.2020. Epub 2020 Jun 18.
Alternatives to blood for use in transfusion medicine have been investigated for decades. An ideal alternative should improve oxygen (O)-carrying capacity and O delivery and support microvascular blood flow. Previous studies have shown that large-molecular diameter hemoglobin (Hb)-based oxygen carriers (HBOCs) based on polymerized bovine Hb (PolybHb) reduce the toxicity and vasoconstriction of first-generation HBOCs by increasing blood and plasma viscosity and preserving microvascular perfusion. The objective of this study was to examine the impact of PolybHb concentration and therefore O-carrying capacity and solution viscosity on resuscitation from hemorrhagic shock in rats. PolybHb was diafiltered on a 500-kDa tangential flow filtration (TFF) module to remove low-molecular weight (MW) PolybHb molecules from the final product. Rats were hemorrhaged and maintained in hypovolemic shock for 30 min before transfusion of PolybHb at 10 g/dL (PHB10), 5 g/dL (PHB5), or 2.5 g/dL (PHB2.5) concentration, to restore blood pressure to 90% of the animal's baseline blood pressure. Resuscitation restored blood pressure and cardiac function in a PolybHb concentration-dependent manner. Parameters indicative of the heart's metabolic activity indicated that the two higher PolybHb concentrations better restored coronary O delivery compared with the low concentration evaluated. Markers of organ damage and inflammation were highest for PHB10, whereas PHB5 and PHB2.5 showed similar expression of these markers. These studies indicate that a concentration of ~5 g/dL of PolybHb may be near the optimal concentration to restore cardiac function, preserve organ function, and mitigate the toxicity of PolybHb during resuscitation from hemorrhagic shock. Large-molecular diameter polymerized bovine hemoglobin avoided vasoconstriction and impairment of cardiac function during resuscitation from hemorrhagic shock that was seen with previous hemoglobin-based O carriers by increasing blood viscosity in a concentration-dependent manner. Supplementation of O-carrying capacity played a smaller role in maintaining cardiac function than increased blood and plasma viscosity.
几十年来，人们一直在研究输血医学中可替代血液的物质。理想的替代品应能提高氧（O）携带能力和氧输送，并支持微血管血流。先前的研究表明，基于聚合牛血红蛋白（PolybHb）的大分子直径血红蛋白（Hb）基氧载体（HBOCs）通过增加血液和血浆粘度以及维持微血管灌注，降低了第一代HBOCs的毒性和血管收缩作用。本研究的目的是研究PolybHb浓度以及由此产生的O携带能力和溶液粘度对大鼠失血性休克复苏的影响。将PolybHb在500 kDa切向流过滤（TFF）模块上进行渗滤，以从最终产品中去除低分子量（MW）的PolybHb分子。大鼠出血后维持低血容量休克30分钟，然后输注浓度为10 g/dL（PHB10）、5 g/dL（PHB5）或2.5 g/dL（PHB2.5）的PolybHb，以使血压恢复到动物基线血压的90%。复苏以PolybHb浓度依赖性方式恢复血压和心脏功能。表明心脏代谢活动的参数表明，与评估的低浓度相比，两个较高的PolybHb浓度能更好地恢复冠状动脉氧输送。器官损伤和炎症标志物在PHB10时最高，而PHB5和PHB2.5显示这些标志物的表达相似。这些研究表明，在失血性休克复苏过程中，浓度约为5 g/dL的PolybHb可能接近恢复心脏功能、保护器官功能和减轻PolybHb毒性的最佳浓度。大分子直径的聚合牛血红蛋白通过以浓度依赖性方式增加血液粘度，避免了失血性休克复苏过程中出现的血管收缩和心脏功能损害，而这在先前基于血红蛋白的氧载体中是可见的。与增加血液和血浆粘度相比，补充氧携带能力在维持心脏功能方面所起的作用较小。
