title: HBOC vasoactivity: interplay between nitric oxide scavenging and capacity to generate bioactive nitric oxide species.
abstract: CONCLUSIONS
  Despite many advances in blood substitute research, the development of materials that are effective in maintaining blood volume and oxygen delivery remains a priority for emergency care and trauma. Clinical trials on hemoglobin (Hb)-based oxygen carriers (HBOCs) have not provided information on the mechanism of toxicity, although all commercial formulations have safety concerns. Specifically, it is important to reconcile the different hypotheses of Hb toxicity, such as nitric oxide (NO) depletion and oxidative reactions, to provide a coherent molecular basis for designing a safe HBOC.
  
  
  BACKGROUND
  HBOCs with different sizes often exhibit differences in the degree of HBOC-induced vasoactivity. This has been attributed to differences in the degree of NO scavenging and in the extent of Hb extravasation. Additionally, it is appears that Hb can undergo reactions that compensate for NO scavenging by generating bioactive forms of NO.
  
  
  RESULTS
  Engineering modifications to enhance bioactive NO production can result in diminished oxygen delivery by virtue of increased oxygen affinity. This strategy can prevent the HBOC from fulfilling the intended goal on preserving oxygenation; however, the NO production effects will increase perfusion and oxygen transport.
  
  
  CONCLUSIONS
  Hb modifications influence NO scavenging and the capacity of certain HBOCs to compensate for NO scavenging through nitrite-mediated reactions that generate bioactive NO. Based on the current understanding of these NO-related factors, possible synthetic strategies are presented that address how HBOC formulations can be prepared that: (i) effectively deliver oxygen, (ii) maintain tissue perfusion, and (iii) limit/reverse underlying inflammation within the vasculature.
authors.affiliation: Department of Bioengineering, University of California, San Diego, CA, USA. pcabrales@ucsd.edu
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.forename: Joel M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D001802:Blood Substitutes / Q000737:chemistry / Q000378:metabolism; D001808:Blood Vessels / Q000502:physiology*; D016166:Free Radical Scavengers / Q000378:metabolism; D006454:Hemoglobins / Q000502:physiology*; D006801:Humans; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D009572:Nitrite Reductases / Q000378:metabolism; D010100:Oxygen / Q000097:blood*; D026361:Reactive Nitrogen Species / Q000378:metabolism
chemical_list: D001802:Blood Substitutes; D016166:Free Radical Scavengers; D006454:Hemoglobins; D026361:Reactive Nitrogen Species; D009569:Nitric Oxide; D009572:Nitrite Reductases; D010100:Oxygen