Red blood cells induce necroptosis of lung endothelial cells and increase susceptibility to lung inflammation

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. To determine the mechanisms of lung endothelial cell (EC) Hig...

Full description

Saved in:
Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2014-12, Vol.190 (11), p.1243-1254
Main Authors: Qing, Danielle Y, Conegliano, David, Shashaty, Michael G S, Seo, Jeongyun, Reilly, John P, Worthen, G Scott, Huh, Dongeun, Meyer, Nuala J, Mangalmurti, Nilam S
Format: Article
Language:English
Subjects:
Animals
Blood
Cell death
Critical Illness
Disease Models, Animal
Endothelial Cells - pathology
Erythrocyte Transfusion - adverse effects
HMGB1 Protein - immunology
HMGB1 Protein - physiology
Human subjects
Humans
In Vitro Techniques
Inflammation
Kinases
Lung - pathology
Mice
Middle Aged
Necrosis
Original
Plasma
Pneumonia - etiology
Respiratory distress syndrome
Respiratory Distress Syndrome, Adult - etiology
Sepsis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201406-1095oc