High-mobility group box 1 contributes to lethality of endotoxemia in heme oxygenase-1-deficient mice

Rina Takamiya, Chi Chih Hung, Sean R. Hall, Koichi Fukunaga, Takashi Nagaishi, Toshitaka Maeno, Caroline Owen, Alvaro A. Macias, Laura E. Fredenburgh, Akitoshi Ishizaka, Richard S. Blumberg, Rebecca M. Baron, Mark A. Perrella

Research output: Contribution to journalArticle

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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 systemicinflammatory 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 HMGB1contribute to endotoxin-induced mortality in the absence of HO-1.

Original languageEnglish
Pages (from-to)129-135
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume41
Issue number2
DOIs
Publication statusPublished - 2009 Aug 1

Fingerprint

Heme Oxygenase-1
Endotoxemia
Tissue
Anti-Inflammatory Agents
Biliverdine
HMGB1 Protein
Carbon Monoxide
Nuclear Proteins
Neutralizing Antibodies
Heme
Metabolism
Endotoxins
Sepsis
Pneumonia
Antioxidants
Genes
Inflammation
Plasmas

Keywords

  • Endotoxemia
  • Heme oxygenase-1
  • High-mobility group box 1
  • Inflammation
  • Oxidative stress

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

High-mobility group box 1 contributes to lethality of endotoxemia in heme oxygenase-1-deficient mice. / Takamiya, Rina; Hung, Chi Chih; Hall, Sean R.; Fukunaga, Koichi; Nagaishi, Takashi; Maeno, Toshitaka; Owen, Caroline; Macias, Alvaro A.; Fredenburgh, Laura E.; Ishizaka, Akitoshi; Blumberg, Richard S.; Baron, Rebecca M.; Perrella, Mark A.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 41, No. 2, 01.08.2009, p. 129-135.

Research output: Contribution to journalArticle

Takamiya, R, Hung, CC, Hall, SR, Fukunaga, K, Nagaishi, T, Maeno, T, Owen, C, Macias, AA, Fredenburgh, LE, Ishizaka, A, Blumberg, RS, Baron, RM & Perrella, MA 2009, 'High-mobility group box 1 contributes to lethality of endotoxemia in heme oxygenase-1-deficient mice', American Journal of Respiratory Cell and Molecular Biology, vol. 41, no. 2, pp. 129-135. https://doi.org/10.1165/rcmb.2008-0331OC
Takamiya, Rina ; Hung, Chi Chih ; Hall, Sean R. ; Fukunaga, Koichi ; Nagaishi, Takashi ; Maeno, Toshitaka ; Owen, Caroline ; Macias, Alvaro A. ; Fredenburgh, Laura E. ; Ishizaka, Akitoshi ; Blumberg, Richard S. ; Baron, Rebecca M. ; Perrella, Mark A. / High-mobility group box 1 contributes to lethality of endotoxemia in heme oxygenase-1-deficient mice. In: American Journal of Respiratory Cell and Molecular Biology. 2009 ; Vol. 41, No. 2. pp. 129-135.
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