{"title":"Pegylated hemoglobins mechanisms to avoid vasoconstriction and maintain perfusion","authors":"P. Cabrales, J. Friedman","doi":"10.1111/J.1778-428X.2007.00090.X","DOIUrl":null,"url":null,"abstract":"SUMMARY \n \n \nDespite the advances in blood substitutes, the development of materials that are effective in maintaining blood volume and oxygen delivery remains the priority for emergency care and trauma. Vasoactivity, i.e. vasoconstriction, presumably caused by nitric oxide (NO) scavenging has been defined as the principal problem associated with acellular hemoglobin (Hb) with low hydrodynamic radius. Conversely, Hb-based materials with very large hydrodynamic radius, achieved by surface decoration of the Hb tetramer with water-trapping polymers such as polyethylene glycol (PEG) conjugation, have been found vasoinactive in spite of being effective NO scavengers. This article explores possible mechanisms for why PEGylated Hbs not only are not vasoconstrictive but also are actually facilitators for maintaining high perfusion levels in the microcirculation. The most promising mechanisms are based on relatively recent observations and models; they indicate that Hb can actively regulate availability of ‘bioactive’ NO forms. This regulation can occur via: (i) NO transport by Hb in an allosterically controlled reversible chemical reaction with the Cys beta 93 (S-NO-Hb); and (ii) production of bioactive forms of NO through nitrite reductase activity of deoxyHb. The principal issues associated with these proposed mechanisms are: (i) how these reactions generate bio-available NO and (ii) how the generated NO is delivered to the site of action without being either degraded or sequestered. We present a promising hypothesis and preliminary supporting data that PEGylated Hbs through a nitrite-mediated reaction are especially effective in generating nitrosothiols, creating a transportable source of bioactive NO.","PeriodicalId":90375,"journal":{"name":"Transfusion alternatives in transfusion medicine : TATM","volume":"9 1","pages":"281-293"},"PeriodicalIF":0.0000,"publicationDate":"2007-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/J.1778-428X.2007.00090.X","citationCount":"15","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Transfusion alternatives in transfusion medicine : TATM","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1111/J.1778-428X.2007.00090.X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 15
Abstract
SUMMARY
Despite the advances in blood substitutes, the development of materials that are effective in maintaining blood volume and oxygen delivery remains the priority for emergency care and trauma. Vasoactivity, i.e. vasoconstriction, presumably caused by nitric oxide (NO) scavenging has been defined as the principal problem associated with acellular hemoglobin (Hb) with low hydrodynamic radius. Conversely, Hb-based materials with very large hydrodynamic radius, achieved by surface decoration of the Hb tetramer with water-trapping polymers such as polyethylene glycol (PEG) conjugation, have been found vasoinactive in spite of being effective NO scavengers. This article explores possible mechanisms for why PEGylated Hbs not only are not vasoconstrictive but also are actually facilitators for maintaining high perfusion levels in the microcirculation. The most promising mechanisms are based on relatively recent observations and models; they indicate that Hb can actively regulate availability of ‘bioactive’ NO forms. This regulation can occur via: (i) NO transport by Hb in an allosterically controlled reversible chemical reaction with the Cys beta 93 (S-NO-Hb); and (ii) production of bioactive forms of NO through nitrite reductase activity of deoxyHb. The principal issues associated with these proposed mechanisms are: (i) how these reactions generate bio-available NO and (ii) how the generated NO is delivered to the site of action without being either degraded or sequestered. We present a promising hypothesis and preliminary supporting data that PEGylated Hbs through a nitrite-mediated reaction are especially effective in generating nitrosothiols, creating a transportable source of bioactive NO.