HMGB1 in Hyperoxia-Induced Impairment of
Pseudomonas aeruginosa Phagocytosis
Lin Mantell, Department of
Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions
Tahereh Entezari-Zaher, Edmund J. Miller,
Haichao Wang, Kevin J. Tracey, JianHua Li, The Feinstein
Institute for Medical Research, North Shore-LIJ Health System,
NY
Abstract
Pseudomonas Aeruginosa (PA) is a leading cause of nosocomial
pneumonia in patients receiving mechanical ventilation with
hyperoxia. Alveolar macrophages are instrumental in bacterial
clearance in the lung. Previously, we have shown that hyperoxic
exposure (≥95% O2) results in a significant impairment of
phagocytosis of PA in both alveolar macrophages that were isolated
from hyperoxic mice and in cultured macrophages. Since patients are
weaned from these high concentrations of oxygen at the earliest
possibility, we tested whether the magnitude of the impairment of
PA phagocytosis depends on the concentrations of oxygen. RAW 264.7
cells were exposed to different concentrations of oxygen, ranging
from 95% down to 40%. Hyperoxia (≥95% O2)-induced cell
proliferation-arrest was diminished when the concentration of
oxygen was 65% or lower. However, this differential effect on cell
proliferation was not reflected in the macrophage’s ability to
phagocytose PA. Exposure to ≥40% O2 induced similar extents of PA
phagocytosis impairment. Corresponding to the reduction in PA
phagocytosis, similar levels of HMGB1, a newly discovered cytokine
and an important contributor to the pathogenesis of hyperoxic acute
lung injury, were accumulated in the cultured media of RAW cells
exposed to various concentrations of hyperoxia. To test whether
HMGB1 contributes to hyperoxia-induced reduction of PA
phagocytosis, RAW cells were exposed to recombinant HMGB1. Compared
to RAW cells treated with a control peptide or trypsinized HMGB1,
recombinant HMGB1 caused a reduction of PA phagocytosis at a
similar level as those exposed to hyperoxia. These data suggest
that HMGB1 plays a critical role in hyperoxia-induced impairment of
PA clearance.