High-mobility group box 1 (
HMGB1) is a
nuclear protein that has been found to be a critical mediator of lethality in
endotoxemia and
sepsis. During the systemic inflammatory response, circulating levels of
HMGB1 are increased, but in a delayed fashion compared with early inflammatory mediators. To counteract the inflammatory response of
endotoxemia, a secondary anti-inflammatory response ensues in an attempt to prevent
inflammation-induced tissue injury. One such cytoprotective gene that is induced during
endotoxemia is
heme oxygenase (HO)-1. HO-1, and its products of
heme metabolism, possess anti-inflammatory and
antioxidant properties to counter the damaging effects of
endotoxemia. In the present study, we wanted to determine whether tissue and circulating levels of
HMGB1 are increased further in the absence of HO-1 during
endotoxemia, and whether this increase may contribute to the pathobiology of
endotoxemia.
Lung inflammation,
HMGB1 protein levels, and expression of
HMGB1 in inflammatory cells were increased in HO-1(-/-) mice compared with HO-1+/+ mice. After the administration of LPS, tissue levels of
HMGB1 were not increased further in HO-1(-/-) mice; however, circulating levels of
HMGB1 were higher when compared with HO-1+/+ mice. HO-1(-/-) mice treated with a
carbon monoxide-releasing molecule or
biliverdin showed a reduction in plasma
HMGB1, which was associated with a marked improvement in survival. HO-1(-/-) mice given HMGB1-neutralizing antibody showed improvement in survival compared with control antibody. These data suggest that exaggerated circulating levels of
HMGB1 contribute to
endotoxin-induced mortality in the absence of HO-1.