title: High-mobility group box 1 contributes to lethality of endotoxemia in heme oxygenase-1-deficient mice.
abstract: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA.
authors.forename: Rina
authors.initials: R
authors.lastname: Takamiya
authors.forename: Chi-Chih
authors.initials: CC
authors.lastname: Hung
authors.forename: Sean R
authors.initials: SR
authors.lastname: Hall
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagaishi
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Maeno
authors.forename: Caroline
authors.initials: C
authors.lastname: Owen
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Macias
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
mesh_terms: D000818:Animals; D001664:Biliverdine / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D019446:Endotoxemia / Q000378:metabolism / Q000401:mortality; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D015996:Survival Rate
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D001664:Biliverdine