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.
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. Lung inflammation, HMGB1 protein levels, and expression of HMGB1 in inflammatory cells were increased in HO-1 −/− mice compared with HO-1 +/+ mice. 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. HO-1, and its products of heme metabolism, possess anti-inflammatory and antioxidant properties to counter the damaging effects of endotoxemia. One such cytoprotective gene that is induced during endotoxemia is heme oxygenase (HO)-1. To counteract the inflammatory response of endotoxemia, a secondary anti-inflammatory response ensues in an attempt to prevent inflammation-induced tissue injury. During the systemic inflammatory response, circulating levels of HMGB1 are increased, but in a delayed fashion compared with early inflammatory mediators. 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.