P-144 - The redox regulation of damage-associated molecular pattern molecule HMGB1 in pulmonary disease

Abstract

HMGB1 is an endogenous molecule that can initiate and perpetuate inflammation. Previously, we have shown that airway HMGB1 mediates hyperoxia-induced acute lung injury and compromised innate immunity in cystic fibrosis and ventilator-associated pneumonia. To determine the redox state of HMGB1 and its effects on acute lung injury and innate immunity under hyperoxic conditions, LC-MS/MS was used to analyze HMGB1 in either bronchoalveolar lavage fluid (BAL) of mice or media of cultured macrophages exposed to 95–99% O2. MS/MS analysis indicated nuclear HMGB1 in both 95% and 21% O2 groups was in its reduced form, but in BAL or culture media, all three critical redox forms of HMGB1 were present. Extracellular HMGB1 was not detected in BAL or cultured macrophages that remained at 21% O2. GTS -21, a drug which can improve macrophage functions and alleviate hyperoxia-induced acute lung injury, kept extracellular HMGB1 in the reduced form. These data suggest that hyperoxia-induced oxidative modifications of HMGB1 occurred after its release into the airways. Strategies to prevent HMGB1 from oxidation may provide an effective approach to treat patients on ventilation with either lung injury and/or compromised host defense against bacterial infections.