Blockade of HMGB1 Inhibits
Hyperoxia-Induced Pro-Inflammatory Lung Injury
Lin Mantell, Department of
Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions, and The Feinstein Institute for Medical Research,
North Shore-LIJ Health System, NY
Mohamm Haichao Javdan, Kevin Tracey, Tahereh
Entezari-Zaher, Edmund Miller, The Feinstein Institute for
Medical Research , North Shore-LIJ Health System, NY
Abstract
Prolonged exposure to hyperoxia results in acute lung injury (ALI)
with markedly elevated levels of proinflammatory cytokines and
infiltrated leukocytes in lungs. However, the mechanisms underlying
hyperoxia-induced proinflammatory ALI remain poorly understood.
Here we report our studies on determining the role of high mobility
group box protein 1 (HMGB1), a newly discovered proinflammatory
cytokine, in hyperoxic lung injury. Exposure of adult mice to
>99% oxygen increased the accumulation of HMGB1 in the
bronchoalveolar lavage fluid, which preceded the onset of severe
lung injury. Neutralizing anti-HMGB1 antibodies, administrated to
mice 24 hours prior to hyperoxic exposure, significantly mitigated
ALI, indicated by the levels of the wet/dry ratio, lung
permeability and total leukocyte infiltration. This protection was
also observed when the treatment with HMGB1 inhibitors was delayed
until after the onset of the oxidative stress. In addition, ethyl
pyruvate, a stable aliphatic antioxidant, not only inhibited HMGB1
secretion from hyperoxic macrophages, but also mitigated hyperoxic
lung injury when administrated post hyperoxic exposure. The
contribution of HMGB1 to the initiation of hyperoxic lung injury
was further confirmed using purified recombinant HMGB1 (rHMGB1)
protein instilled intratreacheally. Administration of rHMGB1 caused
a marked increase in the levels of leukocyte infiltration into the
lung of these mice compared to those that were treated with the
same amounts of non-specific peptide (31±4.8x104 vs. 14±3.4x104,
p<0.05). Taken together, these results indicate that HMGB1 plays
a critical role in mediating hyperoxic lung injury through the
recruitment of leukocytes into the lung, and support the potential
clinical application of HMGB1 inhibitors as therapeutic
interventions against oxidative lung injury in patients receiving
hyperoxia.