Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury

Maria Entezari, Mohammad Javdan, Daniel J. Antoine, Dympna M. P. Morrow, Ravikumar A. Sitapara, Vivek Patel, Mao Wang, Lokesh Sharma, Samir Gorasiya, Michelle Zur, Wenjun Wu, JianHua Li, Huan Yang, Charles R. Ashby, Douglas Thomas, Haichao Wang, Lin L. Mantell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to >= 99% O-2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylatecl and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation. (C) 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)314-322
Number of pages9
JournalRedox biology
Volume2
DOIs
Publication statusPublished - 2014

Keywords

  • Hyperoxia
  • Macrophage
  • HMGB1
  • Hyperacelylauon
  • Redox state
  • MOBILITY GROUP BOX-1
  • RESPIRATORY-DISTRESS-SYNDROME
  • CELL-DEATH
  • MECHANICAL VENTILATION
  • THERAPEUTIC TARGET
  • EPITHELIAL-CELLS
  • PROTEIN
  • APOPTOSIS
  • SEPSIS
  • CYTOKINE

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