Department of Bioengineering, University of California, San Diego, California, United States.
William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, United States.
J Appl Physiol (1985). 2024 Oct 1;137(4):934-944. doi: 10.1152/japplphysiol.00315.2024. Epub 2024 Aug 15.
Unfortunately, during pathological conditions resulting in chronic hemolysis cell-free hemoglobin (Hb) is released into the circulation that releases free heme, resulting in several complications. One approach to prevent these toxicities is the administration of supplemental scavenger proteins, haptoglobin (Hp) and hemopexin (Hpx). The goal of this body of work is to objectively measure the levels of vascular reactivity and inflammatory profiles after an infusion of acellular hemoglobin in animals that were given a coadministration of PEGylated human apohemoglobin (PEG-apoHb), a hemopexin (Hpx)-mimetic that can scavenge free heme from hemoglobin, together with human plasma-derived Hp that can scavenge dimerized Hb. Using intravital microscopy, Golden Syrian hamsters instrumented with a dorsal window chamber were used to evaluate the in vivo effects of four experimental groups that were then challenged with a hypovolemic injection (10% of the animal's blood volume) of human Hb (hHb, 5 g/dL). The four experimental groups consisted of: ) lactated Ringer's solution (control), ) PEG-apoHb only, ) Hp only, and ) PEG-apoHb + Hp. The microvascular hemodynamics (diameter and flow) in arterioles and venules were recorded at baseline, 20 min after treatment, and 20 min after hHb challenge. Systemic parameters (blood pressure and heart rate), blood gases (pH, Pco, and Po), blood parameters (Hb concentration and hematocrit), and multiorgan functionality/inflammation were also measured. Our results suggest that coadministration of PEG-apoHb + Hp as a booster before the infusion of acellular hemoglobin significantly prevented vasoconstriction in the microcirculation, significantly increased the number of functional capillaries, and significantly reduced inflammation. Coadministration of PEGylated human apohemoglobin (PEG-apoHb)-a hemopexin (Hpx) mimetic that can scavenge free heme-and human plasma-derived haptoglobin (Hp) that can scavenge hemoglobin (Hb), reduces microcirculatory dysfunction and cardiac and kidney inflammation in a Hb-challenge model.
不幸的是，在导致慢性溶血的病理条件下，无细胞血红蛋白 (Hb) 会释放到循环中，释放出游离血红素，从而导致多种并发症。一种预防这些毒性的方法是补充清除蛋白，即结合珠蛋白 (Hp) 和血红素结合蛋白 (Hpx)。本研究旨在客观测量在给予聚乙二醇化人脱辅基血红蛋白 (PEG-apoHb) 联合人血浆来源结合珠蛋白（Hp）和血红素结合蛋白（Hpx）模拟物的情况下，无细胞血红蛋白输注后动物血管反应性和炎症谱的变化。使用活体显微镜，对接受背部窗口室仪器操作的金叙利亚仓鼠进行实验，以评估四种实验组的体内效应，然后对其进行低血容量注射（动物血液量的 10%）人类血红蛋白 (hHb，5 g/dL) 的挑战。这四个实验组分别是：）乳酸林格氏液（对照组），）PEG-apoHb 单独，）Hp 单独，）PEG-apoHb + Hp。在基线、治疗后 20 分钟和 hHb 挑战后 20 分钟记录小动脉和小静脉的微血管血液动力学（直径和流量）。还测量了系统参数（血压和心率）、血气（pH、Pco 和 Po）、血液参数（Hb 浓度和血细胞比容）和多器官功能/炎症。我们的结果表明，在输注无细胞血红蛋白之前，联合使用 PEG-apoHb + Hp 作为佐剂，可显著预防微血管血管收缩，显著增加功能毛细血管数量，并显著减少炎症。联合使用聚乙二醇化人脱辅基血红蛋白（PEG-apoHb）-一种可清除游离血红素的血红素结合蛋白（Hpx）模拟物和可清除血红蛋白（Hb）的人血浆来源结合珠蛋白（Hp）可减少血红蛋白挑战模型中的微循环功能障碍以及心脏和肾脏炎症。
