title: Red blood cells induce necroptosis of lung endothelial cells and increase susceptibility to lung inflammation.
abstract: BACKGROUND
  Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown.
  
  
  OBJECTIVE
  To determine the mechanisms of lung endothelial cell (EC) High Mobility Group Box 1 (HMGB1) release following exposure to RBCs and to determine whether RBC transfusion increases susceptibility to lung inflammation in vivo through release of the danger signal HMGB1.
  
  
  METHODS
  In vitro studies examining human lung EC viability and HMGB1 release following exposure to allogenic RBCs were conducted under static conditions and using a microengineered model of RBC perfusion. The plasma from transfused and nontransfused patients with severe sepsis was examined for markers of cellular injury. A murine model of RBC transfusion followed by LPS administration was used to determine the effects of RBC transfusion and HMGB1 release on LPS-induced lung inflammation.
  
  
  RESULTS
  After incubation with RBCs, lung ECs underwent regulated necrotic cell death (necroptosis) and released the essential mediator of necroptosis, receptor-interacting serine/threonine-protein kinase 3 (RIP3), and HMGB1. RIP3 was detectable in the plasma of patients with severe sepsis, and was increased with blood transfusion and among nonsurvivors of sepsis. RBC transfusion sensitized mice to LPS-induced lung inflammation through release of the danger signal HMGB1.
  
  
  CONCLUSIONS
  RBC transfusion enhances susceptibility to lung inflammation through release of HMGB1 and induces necroptosis of lung EC. Necroptosis and subsequent danger signal release is a novel mechanism of injury following transfusion that may account for the increased risk of ARDS in critically ill transfused patients.
authors.affiliation: 1 Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, and.
authors.forename: Danielle Y
authors.initials: DY
authors.lastname: Qing
authors.forename: David
authors.initials: D
authors.lastname: Conegliano
authors.forename: Michael G S
authors.initials: MG
authors.lastname: Shashaty
authors.forename: Jeongyun
authors.initials: J
authors.lastname: Seo
authors.forename: John P
authors.initials: JP
authors.lastname: Reilly
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
authors.forename: Dongeun
authors.initials: D
authors.lastname: Huh
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.forename: Nilam S
authors.initials: NS
authors.lastname: Mangalmurti
mesh_terms: D000818:Animals; D016638:Critical Illness; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology*; D017707:Erythrocyte Transfusion / Q000009:adverse effects*; D024243:HMGB1 Protein / Q000276:immunology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D009336:Necrosis; D011014:Pneumonia / Q000209:etiology*; D012128:Respiratory Distress Syndrome / Q000209:etiology*
chemical_list: D024243:HMGB1 Protein
keywords: HMGB1; RBC transfusion; RIP3; endothelial; necroptosis