title: First-generation blood substitutes: what have we learned? Biochemical and physiological perspectives.
abstract: Chemically modified or recombinant hemoglobin (Hb)-based oxygen carriers (HBOCs) have been developed as oxygen therapeutics or 'blood substitutes' for use in a variety of clinical settings. Oxidative and nitrosative reactions of acellular Hb can limit the effectiveness and compromise the safety of HBOCs. The reactions between Hb and biologically relevant redox active molecules may also perturb redox sensitive signaling pathways. In recent years, systematic in vitro and in vivo structural and functional evaluation of several HBOCs has been carried out and, in some cases, delineated the 'structural' origin of their toxicity. This enables potential protective strategies against Hb-mediated side reactions to be rationally suggested. Here the authors provide an overview of their research experiences, novel insights into the molecular basis of toxicities of these products and some lessons learned.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, National Institutes of Health Campus, Bethesda, MD 20892, USA. abdu.alayash@fda.hhs.gov
authors.forename: Abdu I
authors.initials: AI
authors.lastname: Alayash
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
mesh_terms: D000818:Animals; D001802:Blood Substitutes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D015202:Protein Engineering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D009569:Nitric Oxide