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

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% O2 (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 hyperacetylated 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.

• Authors: 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
• Journal: Redox biology (Redox Biol) Vol. 2 Pg. 314-22 ( 2014) ISSN: 2213-2317 [Print] Netherlands
• PMID: 24563849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies
• HMGB1 Protein
• HMGB1 protein, mouse
• Pyruvates
• ethyl pyruvate

Topics

• Acetylation
• Acute Lung Injury (chemically induced, immunology, pathology, therapy)
• Animals
• Antibodies (administration & dosage)
• Bronchoalveolar Lavage Fluid (immunology)
• Cell Hypoxia
• Cell Line
• Disease Models, Animal
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Injections, Spinal
• Lung (cytology, immunology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophils (metabolism)
• Pyruvates (administration & dosage)