Title |
Inhibition of High-Mobility Group Box 1 Protein (HMGB1) Enhances Bacterial Clearance and Protects against Pseudomonas Aeruginosa Pneumonia in Cystic Fibrosis
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Published in |
Molecular Medicine, February 2012
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DOI | 10.2119/molmed.2012.00024 |
Pubmed ID | |
Authors |
Maria Entezari, Daniel J Weiss, Ravikumar Sitapara, Laurie Whittaker, Matthew J Wargo, JianHua Li, Haichao Wang, Huan Yang, Lokesh Sharma, Binh D Phan, Mohammad Javdan, Sangeeta S Chavan, Edmund J Miller, Kevin J Tracey, Lin L Mantell |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Australia | 1 | 2% |
Canada | 1 | 2% |
Unknown | 47 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 14 | 29% |
Student > Ph. D. Student | 14 | 29% |
Student > Bachelor | 6 | 12% |
Professor | 4 | 8% |
Student > Master | 3 | 6% |
Other | 6 | 12% |
Unknown | 2 | 4% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 17 | 35% |
Agricultural and Biological Sciences | 9 | 18% |
Immunology and Microbiology | 5 | 10% |
Biochemistry, Genetics and Molecular Biology | 3 | 6% |
Chemistry | 3 | 6% |
Other | 7 | 14% |
Unknown | 5 | 10% |