Binh D Phan

New York College of Health Professions, New York City, New York, United States

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Publications (4)16.28 Total impact

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    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 ventilator-associated 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.
    American Journal of Respiratory Cell and Molecular Biology 10/2012; 48(3). DOI:10.1165/rcmb.2012-0279OC · 3.99 Impact Factor
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    ABSTRACT: Pulmonary infection with Pseudomonas aeruginosa and neutrophilic lung inflammation significantly contribute to morbidity and mortality in cystic fibrosis (CF). High-mobility group box 1 protein (HMGB1), a ubiquitous DNA binding protein that promotes inflammatory tissue injury, is significantly elevated in CF sputum. However, its mechanistic and potential therapeutic implications in CF were previously unknown. We found that HMGB1 levels were significantly elevated in bronchoalveolar lavage fluids (BALs) of CF patients and cystic fibrosis transmembrane conductance regulator (CFTR )(-/-) mice. Neutralizing anti-HMGB1 monoclonal antibody (mAb) conferred significant protection against P. aeruginosa-induced neutrophil recruitment, lung injury and bacterial infection in both CFTR(-/-) and wild-type mice. Alveolar macrophages isolated from mice treated with anti-HMGB1 mAb had improved phagocytic activity, which was suppressed by direct exposure to HMGB1. In addition, BAL from CF patients significantly impaired macrophage phagocytotic function, and this impairment was attenuated by HMGB1-neutralizing antibodies. The HMGB1-mediated suppression of bacterial phagocytosis was attenuated in macrophages lacking toll-like receptor (TLR)-4, suggesting a critical role for TLR4 in signaling HMGB1-mediated macrophage dysfunction. These studies demonstrate that the elevated levels of HMGB1 in CF airways are critical for neutrophil recruitment and persistent presence of P. aeruginosa in the lung. Thus, HMGB1 may provide a therapeutic target for reducing bacterial infection and lung inflammation in CF.
    Molecular Medicine 02/2012; 18(1):477-85. DOI:10.2119/molmed.2012.00024 · 4.51 Impact Factor
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    ABSTRACT: Mechanical ventilation with hyperoxia is a necessary treatment for patients with respiratory distress. However, patients on mechanical ventilation have increased susceptibility to infection. Studies including ours have shown that reactive oxygen species (ROS), generated by exposure to prolonged hyperoxia, can cause a decrease in the phagocytic activity of alveolar macrophages. Hydrogen peroxide (H₂O₂) is a form of ROS generated under hyperoxic conditions. In this study, we examined whether treatment with H₂O₂ directly affects macrophage phagocytic ability in RAW 264.7 cells that were exposed to either 21% O₂ (room air) or 95% O₂ (hyperoxia). Moderate concentrations (ranging from 10 to 250 μM) of H₂O₂ significantly enhanced macrophage phagocytic activity and restored hyperoxia-suppressed phagocytosis through attenuation of hyperoxia-induced disorganization of actin cytoskeleton and actin oxidation. These results indicate that H₂O₂ at low-moderate concentrations can be beneficial to host immune responses by improving macrophage phagocytic activity.
    Journal of Immunotoxicology 02/2011; 8(1):3-9. DOI:10.3109/1547691X.2010.531063 · 2.05 Impact Factor

  • Free Radical Biology and Medicine 12/2010; 49. DOI:10.1016/j.freeradbiomed.2010.10.412 · 5.74 Impact Factor