This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2008-0331OCv1 41/2/129    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takamiya, R. Articles by Perrella, M. A. Search for Related Content PubMed PubMed Citation Articles by Takamiya, R. Articles by Perrella, M. A.

High-Mobility Group Box 1 Contributes to Lethality of Endotoxemia in Heme Oxygenase-1–Deficient Mice

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, ² Newborn Medicine, and ³ Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ⁴ Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan; ⁵ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan; and ⁶ Division of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Mark A. Perrella, M.D., Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. E-mail: mperrella{at}rics.bwh.harvard.edu

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.

Key Words: endotoxemia • heme oxygenase-1 • inflammation • high-mobility group box 1 • oxidative stress

CLINICAL RELEVANCE These results may have implications for patients at increased risk for inflammation and oxidative stress. A deficiency of heme oxygenase (HO)-1 leads to increased lung inflammation and enhanced release of HMGB1 during endotoxemia. These data provide further insight into the pathophysiology of endotoxemia, and additional support for the therapeutic potential of HO-1–derived heme metabolites in inflammatory disease processes.

 

This article has been cited by other articles:

				I. Garcia-Arnandis, M. I. Guillen, M. A. Castejon, F. Gomar, and M. J. Alcaraz Haem oxygenase-1 down-regulates high mobility group box 1 and matrix metalloproteinases in osteoarthritic synoviocytes Rheumatology, January 27, 2010; (2010): kep463v1 - kep463. [Abstract] [Full Text] [PDF]

				K. Tsoyi, T. Y. Lee, Y. S. Lee, H. J. Kim, H. G. Seo, J. H. Lee, and K. C. Chang Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo Mol. Pharmacol., July 1, 2009; 76(1): 173 - 182. [Abstract] [Full Text] [PDF]