title: High Mobility Group Box-1 mediates hyperoxia-induced impairment of Pseudomonas aeruginosa clearance and inflammatory lung injury in mice.
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 exhibit enhanced susceptibility to infections and develop ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most common species of bacteria found in these patients. Previously, we demonstrated that prolonged exposure to hyperoxia can compromise the ability of alveolar macrophages (AMs), an essential part of the innate immunity, to phagocytose PA. This study sought to investigate the potential molecular mechanisms underlying hyperoxia-compromised innate immunity against bacterial infection in a murine model of PA pneumonia. Here, we show that exposure to hyperoxia (≥ 99% O2) led to a significant elevation in concentrations of airway high mobility group box-1 (HMGB1) and increased mortality in C57BL/6 mice infected with PA. Treatment of these mice with a neutralizing anti-HMGB1 monoclonal antibody (mAb) resulted in a reduction in bacterial counts, injury, and numbers of neutrophils in the lungs, and an increase in leukocyte phagocytic activity compared with mice receiving control mAb. This improved phagocytic function was associated with reduced concentrations of airway HMGB1. The correlation between phagocytic activity and concentrations of extracellular HMGB1 was also observed in cultured macrophages. These results indicate a pathogenic role for HMGB1 in hyperoxia-induced impairment with regard to a host's 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.
authors.affiliation: Division of Cardiopulmonary Toxicology, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA.
authors.forename: Vivek S
authors.initials: VS
authors.lastname: Patel
authors.forename: Ravikumar A
authors.initials: RA
authors.lastname: Sitapara
authors.forename: Ashwini
authors.initials: A
authors.lastname: Gore
authors.forename: Binh
authors.initials: B
authors.lastname: Phan
authors.forename: Lokesh
authors.initials: L
authors.lastname: Sharma
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sampat
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Sangeeta S
authors.initials: SS
authors.lastname: Chavan
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Lin L
authors.initials: LL
authors.lastname: Mantell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000382:microbiology; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D018496:Hyperoxia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology / Q000502:physiology; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D053717:Pneumonia, Ventilator-Associated / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000378:metabolism*; D012121:Respiration, Artificial / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D024243:HMGB1 Protein