%0 Journal Article
%T Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study
%A Angela P. Brandon
%A Brant M. Wagener
%A Charity Morgan
%A Cilina A. Evans
%A Jaideep Honavar
%A Jean-Francois Pittet
%A Jeffrey D. Kerby
%A Jillian R. Richter
%A Joo-Yeun Oh
%A Judy Creighton
%A Marisa B. Marques
%A Parker J. Hu
%A Rakesh P. Patel
%A Randal O. Dull
%A Shannon W. Stephens
%J PLOS Medicine: A Peer-Reviewed Open-Access Journal
%D 2018
%R https://doi.org/10.1371/journal.pmed.1002522
%X Trauma is the leading cause of death and disability in patients aged 1每46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood. We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean [95% CI] 106.4 米l [88.5每124.3] for fresh RBCs and 192.5 米l [140.9每244.0] for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean [95% CI] 1.2 ℅ 107 [ˋ1.0 ℅ 107 to 2.5 ℅ 107] for fresh RBCs and 3.6 ℅ 107 [2.5 ℅ 107 to 4.7 ℅ 107] for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa每induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean [95% CI] 15.4 ng/ml [6.7每24.0] for fresh RBCs and 50.3 ng/ml [12.3每88.2] for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar每millimolar
%U https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002522