Site-specific modifications and toxicity of blood substitutes

D’Agnillo, Felice; Alayash, Abdu I.

doi:10.1016/s0169-409x(99)00050-2

Cited by 54 publications

(49 citation statements)

References 62 publications

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“…Nitrite-induced oxidation of air-equilibrated HBOCs can also be a source of MetHb and ferryl Hb (20). Cellular toxicity attributed to ferryl heme includes promotion of lipid peroxidation, lactate dehydrogenase release, and DNA fragmentation; phenomena recognized as markers of cell injury and death by apoptosis and necrosis (43). The E 1/2 values reported in Table 1 show that the low affinity crosslinked HBOCs are intrinsically less readily oxidized than unmodified Hb A 0 .…”

Section: Discussionmentioning

confidence: 99%

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Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

et al. 2007

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SummaryA review of the oxidative and nitrosative reactions of cell-free hemoglobin-based oxygen carriers (HBOCs) shows that these reactions are intimately linked and are subject to allosteric control. Cross-linking reactions used to produce HBOCs introduce conformational constraints and result in Hbs with reduced responses to heterotropic and homotropic allosteric effectors. The Nernst plots of heme oxidation of cross-linked HBOCs are shifted to higher potentials relative to unmodified Hb in the absence of allosteric effectors, in accord with their T-state stabilization and right-shifted Hill plots of O 2 binding. They exhibit enhanced rates of autoxidation and nitrite-induced oxidation, features that appear due to their having more solvent-accessible heme pockets. The stability of their NO-Hb derivatives varies as a result of allosteric effects on the extent of formation of pentacoordinate NO-heme geometry by a chains and subsequent oxidation of partner b chains. The physiological implications of these findings on the safety, efficacy and design of second generation HBOCs are discussed in the framework of a reaction scheme showing linkages between Hbmediated redox reactions. These redox reactions can drive formation of SNO-Hb and other reactive species and are of significance for the use of cell-free Hbs in vivo.

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Section: Discussionmentioning

confidence: 99%

“…It is an analogue of DCLHb TM and has been extensively evaluated as a potential blood substitute (1).…”

Section: Introductionmentioning

confidence: 99%

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

et al. 2007

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“…However, unforeseen difficulties related to safety (3) and efficacy have arisen in clinical trials (4)(5)(6), leading to a need for new materials with specific structural characteristics (7) that can be related to their performance. For example, acellular cross-linked hemoglobin tetramers cause serious problems associated with vasoactivity (8,9).…”

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confidence: 99%

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Kluger

2008

Biochemistry

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Hemoglobin-based oxygen carriers have been sought as stable, sterile alternatives to red cells in transfusions. Problems in clinical trials using cross-linked tetramers have led to proposals that larger assemblies of tetramers may alleviate some of the problems. A study of such assemblies requires materials with defined structures and physical properties. Evaluation of cross-linked bis-tetramers with inflexible linear links between the tetramers revealed that these have very low cooperativity in oxygen binding and would thus be inefficient as oxygen carriers. New, more flexible reagents were designed to cross-link and connect tetramers in two modes: with angular connectors that permit torsional movement (1-3) and with linear connectors that resemble previously studied systems (4-6). The resulting cross-linked bis-tetramers were produced in high yield and were isolated and characterized. Digest mapping showed that modifications were specifically introduced as expected at amino groups in the 2,3-bisphosphoglycerate binding sites within beta subunits. Circular dichroism showed that the secondary structure of the globin chains is maintained while the microenvironment of the hemes is altered. The bis-tetramers derived from 1-3 have oxygen affinity (P(50) = 3.6-4.7) and cooperativity (n(50) = 2.2-2.7) that appear to be suitable for efficient oxygen delivery to hypoxic regions along with increased mass that is expected to minimize extravasation.

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“…The heme then releases free iron that may catalyze production of the hydroxyl radical by the Fenton reaction, thus increasing the ROS concentration ( Figure 10). Alternatively, the functional form of hemoglobin, that contains iron in the ferrous state, may react with H 2 O 2 to produce the ferryl hemoglobin radical and the hydroxyl radical (31). Rats that had received Se would have a higher concentration of glutathione peroxidase in their epithelial cells, and so it is probable that the initial formation of excess ROS, caused by ROS scavenger dilution and possible activation of intraepithelial leukocytes, would be reduced in Se rats.…”

Section: Discussionmentioning

confidence: 99%

“…These include (1) the reaction of H 2 O 2 with hemoglobin to give the ferryl and the hydroxyl radicals; (2) the reaction of H 2 O 2 with intracellular cytochrome c, an electron carrier in the respiratory chain; or (3) by excess H 2 O 2 alone (32). Excess H 2 O 2 in the tissue would be produced by plasma dilution after injection of HBS-BSA, and by itself would not cause the extensive tissue damage that is perpetrated by the ferryl radical (12,31). Thus, DHR fluorescence can be associated with different species of ROS, some of which produce much more cellular damage than others.…”

Section: Discussionmentioning

confidence: 99%

Selenium Reduces Hemoglobin-Induced Epithelial Damage to Intestinal Mucosa

Baldwin

Wiley²

2002

Artificial Cells, Blood Substitutes, and Biotechnology

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Modified hemoglobins are being considered as possible "blood substitutes." Experiments were performed to determine whether diaspirin cross-linked hemoglobin (DBBF-Hb) produces epithelial damage and whether this is reduced by selenium (Se). Anesthetized Sprague-Dawley rats, half of which received 2 x 10(-6) g/ml Se, daily for 3 weeks, in their drinking water, were injected with a 5 ml bolus of 10 mg/ml DBBF-Hb. Control animals received saline (5 animals per group). After 30 minutes, the intestine was perfusion-fixed for light and electron microscopy. Eighty villi per rat were assigned an epithelial integrity index (E.I.), ranging from 1 (intact) to 3 (some cell-cell and cell-basement membrane separation). In non-Se rats, E.I. was significantly compromised by DBBF-Hb, compared to HBS-BSA (2.47+/-0.57 (SD) vs. 1.36+/-0.49, p<0.001). In Se rats, neither injection with DBBF-Hb or HBS-BSA caused epithelial damage (1.03+/-0.17 vs. 1.07+/-0.26). Mast cell degranulation per villus (MCD) was measured in 60 villi per rat. In non-Se rats, MCD was significantly greater after DBBF-Hb than after HBS-BSA injection (1.83+/-1.42 vs. 0.2+/-0.4). Supplementary Se did not reduce this effect. In fact, MCD was significantly increased in both sets of rats compared to their non-Se counterparts (3.27+/-2.40 and 1.48+/-1.70 for DBBF-Hb and HBS-BSA, respectively). Since mast cell mediators damage cells, Se must protect the mucosal epithelium in some way.

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Site-specific modifications and toxicity of blood substitutes

Cited by 54 publications

References 62 publications

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Selenium Reduces Hemoglobin-Induced Epithelial Damage to Intestinal Mucosa

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