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2014 ; 190
(11
): 1243-54
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Red blood cells induce necroptosis of lung endothelial cells and increase
susceptibility to lung inflammation
#MMPMID25329368
Qing DY
; Conegliano D
; Shashaty MG
; Seo J
; Reilly JP
; Worthen GS
; Huh D
; Meyer NJ
; Mangalmurti NS
Am J Respir Crit Care Med
2014[Dec]; 190
(11
): 1243-54
PMID25329368
show ga
RATIONALE: 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. OBJECTIVES: 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.
MEASUREMENTS AND MAIN 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.
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