Lin L. Mantell

HMGB1 Mediates Hyperoxia-induced Impairment of Pseudomonas aeruginosa Clearance and Inflammatory Lung Injury

Lin L. Mantell, College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences; Graduate Students: Vivek S. Patel and Ravikumar A. Sitapara

Abstract

Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, a significant number of patients on ventilators have enhanced susceptibility to infections and develop ventilatorassociated pneumonia (VAP). Pseudomonas aeruginosa (PA) are one of the most common bacteria found in these patients. Previously, we demonstrated that prolonged exposure to hyperoxia can compromise the ability of alveolar macrophages (AM), an essential part of the innate immunity, to phagocytose PA. The objective of this study was to investigate potential molecular mechanisms underlying hyperoxia-compromised innate immunity against bacterial infection in a mouse model of PA pneumonia. Here, we show that exposure to hyperoxia (≥99% O2) led to a significant elevation in levels of airway HMGB1 and an increased mortality in C57BL/6 mice infected with PA. Treatment of these mice with neutralizing anti-HMGB1 monoclonal antibody (mAb) resulted in a reduction in bacterial counts, injury, and number of neutrophils in the lung and an increase in leukocyte phagocytic activity compared to mice receiving control mAb. This improved phagocyte function was associated with reduced levels of airway HMGB1. The correlation between phagocytic activity and levels of extracellular HMGB1 was also observed in cultured macrophages. These results indicate a pathogenic role for HMGB1 in hyperoxia-induced impairment in host ability to clear bacteria and inflammatory lung injury. Thus, HMGB1 may provide a novel molecular target for improving hyperoxia-compromised innate immunity in patients with VAP.