High mobility group box 1 (
HMGB1) is a novel late mediator of inflammatory responses that contributes to
endotoxin-induced
acute lung injury and
sepsis-associated lethality. Although
acute lung injury is a frequent complication of severe blood loss, the contribution of
HMGB1 to organ system dysfunction in this setting has not been investigated. In this study,
HMGB1 was detected in pulmonary endothelial cells and macrophages under baseline conditions. After
hemorrhage, in addition to positively staining endothelial cells and macrophages, neutrophils expressing
HMGB1 were present in the lungs.
HMGB1 expression in the lung was found to be increased within 4 h of
hemorrhage and then remained elevated for more than 72 h after blood loss. Neutrophils appeared to contribute to the increase in posthemorrhage pulmonary
HMGB1 expression since no change in lung
HMGB1 levels was found after
hemorrhage in mice made neutropenic with
cyclophosphamide. Plasma concentrations of
HMGB1 also increased after
hemorrhage. Blockade of
HMGB1 by administration of anti-HMGB1
antibodies prevented
hemorrhage-induced increases in nuclear translocation of
NF-kappa B in the lungs and pulmonary levels of proinflammatory
cytokines, including keratinocyte-derived
chemokine,
IL-6, and
IL-1 beta. Similarly, both the accumulation of neutrophils in the lung as well as enhanced lung permeability were reduced when anti-HMGB1
antibodies were injected after
hemorrhage. These results demonstrate that
hemorrhage results in increased
HMGB1 expression in the lungs, primarily through neutrophil sources, and that
HMGB1 participates in
hemorrhage-induced
acute lung injury.