High-Mobility Group Box 1 Contributes to Lethality of Endotoxemia in Heme Oxygenase-1–Deficient Mice
- 1 August 2009
- journal article
- Published by American Thoracic Society in American Journal of Respiratory Cell and Molecular Biology
- Vol. 41 (2), 129-135
- https://doi.org/10.1165/rcmb.2008-0331oc
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.Keywords
This publication has 48 references indexed in Scilit:
- Carbon Monoxide and BilirubinAmerican Journal of Respiratory Cell and Molecular Biology, 2007
- The Role of Heme Oxygenase-1 in Pulmonary DiseaseAmerican Journal of Respiratory Cell and Molecular Biology, 2007
- Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1Journal of Leukocyte Biology, 2006
- Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic ApplicationsPhysiological Reviews, 2006
- Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediatorsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2006
- Oxidative stress in sepsis: a redox reduxJCI Insight, 2006
- 30 some years of heme oxygenase: From a “molecular wrecking ball” to a “mesmerizing” trigger of cellular eventsBiochemical and Biophysical Research Communications, 2005
- Biliverdin administration protects against endotoxin-induced acute lung injury in ratsAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2005
- Absence of heme oxygenase‐1 exacerbates atherosclerotic lesion formation and vascular remodelingThe FASEB Journal, 2003
- Transfer of Heme Oxygenase 1 cDNA by a Replication-Deficient Adenovirus Enhances Interleukin 10 Production from Alveolar Macrophages That Attenuates Lipopolysaccharide-Induced Acute Lung Injury in MiceHuman Gene Therapy, 2001