Inhibition of high-mobility group box 1 protein (HMGB1) enhances bacterial clearance and protects against Pseudomonas Aeruginosa pneumonia in cystic fibrosis.

摘要: Pulmonary infection with Pseudomonas aeruginosa and neutrophilic lung inflammation significantly contribute to morbidity mortality in cystic fibrosis (CF). High-mobility group box 1 protein (HMGB1), a ubiquitous DNA binding that promotes inflammatory tissue injury, is elevated CF sputum. However, its mechanistic potential therapeutic implications were previously unknown. We found HMGB1 levels bronchoalveolar lavage fluids (BALs) of patients transmembrane conductance regulator (CFTR)-/- mice. Neutralizing anti-HMGB1 monoclonal antibody (mAb) conferred significant protection against P aeruginosa-induced neutrophil recruitment, injury bacterial both CFTR-/- wild-type Alveolar macrophages isolated from mice treated anti-HMGBl mAb had improved phagocytic activity, which was suppressed by direct exposure HMGB1. In addition, BAL impaired macrophage phagocytotic function, this impairment attenuated HMGB1-neutralizing antibodies. The HMGB1-mediated suppression phagocytosis lacking toll-like receptor (TLR)-4, suggesting critical role for TLR4 signaling dysfunction. These studies demonstrate the airways are recruitment persistent presence P. lung. Thus, may provide target reducing CF.