HMGB1 is a key mediator of anemia in a murine model of sepsis survivors (CCR3P.224)

Abstract

Abstract Anemia is omnipresent in patients with severe sepsis, and correlated to long term outcome. Its mechanism is incompletely understood. High mobility group box 1 (HMGB1) is persistently elevated in murine sepsis survivors. To study the role of HMGB1 in anemia of sepsis, we used a murine model of severe sepsis induced by cecal ligation and puncture (CLP). Anemia developed 3 days after onset of sepsis and persisted for no less than 28 days. The compensatory regenerative response was blunted, as demonstrated by reduced and erratic reticulocytosis. Splenomegaly was present in CLP survivors for as long as the follow up period. Microscopy revealed splenic architecture disruption, with expansion of the red pulp, characteristic of stress erythropoiesis. Analysis of terminal erythroid differentiation using flow cytometry demonstrated an increase in all erythroid progenitors, from proerythroblast to orthochromatic erythroblast, while mature erythroid cell populations were significantly reduced. An anti-HMGB1 (2G7 clone; 50ug/day x3 days I.P.) administered 9 days after after CLP significantly protected septic mice from anemia. In contrast, exogenous administration of HMGB1 (500ug/mouse/day x7d I.P.) to healthy mice was sufficient to induce a significant decrease in hemoglobin (p>0.05) and splenomeglay. These results indicate HMGB1 is necessary and sufficient for developing anemia in murine sepsis, and suggest HMGB1 may be a novel therapeutic target of anemia in sepsis survivors.