title: Impaired adenosine-5'-triphosphate release from red blood cells promotes their adhesion to endothelial cells: a mechanism of hypoxemia after transfusion.
abstract: OBJECTIVE
  Transfusion of red blood cells has been linked to disappointing clinical outcomes in the critically ill, but specific mechanisms of organ dysfunction after transfusion remain poorly understood. We tested the hypothesis that red blood cell storage impairs the ability of red blood cells to release adenosine-5'-triphosphate and that impaired adenosine-5'-triphosphate release was injurious in vivo, in part through increased red blood cell adhesion.
  
  
  METHODS
  Prospective, controlled, mechanistic study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Human and mouse blood donors; nude mouse transfusion recipients.
  
  
  METHODS
  Manipulation of adenosine-5'-triphosphate release, supplemental adenosine-5'-triphosphate, and antibodies to red blood cell and endothelial adhesion receptors were used in vitro and in vivo to probe the roles of released adenosine-5'-triphosphate and adhesion in responses to (transfused) red blood cells.
  
  
  RESULTS
  The ability of stored red blood cells to release adenosine-5'-triphosphate declined markedly within 14 days after collection despite relatively stable levels of adenosine-5'-triphosphate within the red blood cells. Inhibiting adenosine-5'-triphosphate release promoted the adhesion of stored red blood cells to endothelial cells in vitro and red blood cell sequestration in the lungs of transfused mice in vivo. Unlike transfusion of fresh human red blood cells, stored red blood cell transfusion in mice decreased blood oxygenation and increased extravasation of red blood cells into the lung's alveolar air spaces. Similar findings were seen with transfusion of fresh red blood cells treated with the adenosine-5'-triphosphate release inhibitors glibenclamide and carbenoxolone. These findings were prevented by either coinfusion of an adenosine-5'-triphosphate analog or pretransfusion incubation of the red blood cells with an antibody against the erythrocyte adhesion receptor Landsteiner-Wiener (intercellular adhesion molecule-4).
  
  
  CONCLUSIONS
  The normal flow of red blood cells in pulmonary microvessels depends in part on the release of antiadhesive adenosine-5'-triphosphate from red blood cells, and storage-induced deficiency in adenosine-5'-triphosphate release from transfused red blood cells may promote or exacerbate microvascular pathophysiology in the lung, in part through increased red blood cell adhesion.
authors.affiliation: Department of Medicine, Durham Veterans Administration and Duke University Medical Centers, Durham, NC, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhu
authors.forename: Rahima
authors.initials: R
authors.lastname: Zennadi
authors.forename: Bruce X
authors.initials: BX
authors.lastname: Xu
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Eu
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Torok
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McMahon
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D001793:Blood Preservation; D001803:Blood Transfusion; D002229:Carbenoxolone / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004912:Erythrocytes / Q000378:metabolism / Q000502:physiology*; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D013997:Time Factors
chemical_list: D000255:Adenosine Triphosphate; D001081:Apyrase; D002229:Carbenoxolone; D005905:Glyburide