2-O, 3-O desulfated heparin (ODSH) improves bacterial clearance in cystic fibrosis by reducing HMGB1 release and improving phagocytosis of airway macrophages

Increased levels of airway HMGB1, which compromises innate immunity, are reported in patients with cystic fibrosis (CF) and CF animals. In this study, we determined the sources of airway HMGB1, the effects of ODSH on Pseudomonas aeruginosa (PA) clearance in CFTR -/- mice and the mechanisms. Here we show that CF cells, including IB3 epithelia and bone marrow derived macrophages (BMDM) released a significantly greater amount of HMGB1 than their wildtype counterparts at basal level and in the presence of LPS. In addition, IB3 cells produced significantly less NO than control cells upon LPS treatment, alveolar macrophages (AM) and BMDM from CF mice had significantly lower phagocytic activity compared to those from WT mice, suggesting a decreased bacterial clearing capacity in CF. While macrophage phagocytosis from WT mice was reduced by rHMGB1, ODSH, a heparin derivative that inhibits HMGB1 receptor binding, restored such impairment. CF mice administered with ODSH had significantly reduced PA loads in the lungs, with attenuated lung injury. These results demonstrate that airway HMGB1 released by epithelial cells and macrophages impairs innate immunity in CF, by reducing bacterial clearance of macrophages. Such impairment is attenuated by ODSH via targeting airway HMGB1 accumulation.