2-O, 3-O desulfated heparin (ODSH) increases bacterial clearance and attenuates lung injury in cystic fibrosis by restoring HMGB1-compromised macrophage function

Molecular Medicine

Vivek Patel¹  Uday Kiran Velagapudi¹  Charles R. Ashby¹  Mosi Lin¹  LeeAnne Daley¹  Xiaojing Yang¹  Tanaji T. Talele¹  Sung Soo Mun¹  Alex G. Gauthier¹  Jiaqi Wu¹  Mao Wang¹  Lin L. Mantell²  Haichao Wang³  Thomas P. Kennedy⁴ 

[1] Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy and Health Sciences, 11439, Queens, NY, USA;Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy and Health Sciences, 11439, Queens, NY, USA;The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY, USA;The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY, USA;Wake Forest University School of Medicine, Winston Salem, NC, USA;

关键词: Cystic fibrosis;    Pulmonary infection;    HMGB1;    Macrophage functions;    Phagocytosis;    ODSH;    NO;   

DOI  :  10.1186/s10020-021-00334-y

来源: Springer

【 摘 要 】

BackgroundHigh mobility group box 1 protein (HMGB1) is an alarmin following its release by immune cells upon cellular activation or stress. High levels of extracellular HMGB1 play a critical role in impairing the clearance of invading pulmonary pathogens and dying neutrophils in the injured lungs of cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS). A heparin derivative, 2-O, 3-O desulfated heparin (ODSH), has been shown to inhibit HMGB1 release from a macrophage cell line and is efficacious in increasing bacterial clearance in a mouse model of pneumonia. Thus, we hypothesized that ODSH can attenuate the bacterial burden and inflammatory lung injury in CF and we conducted experiments to determine the underlying mechanisms.MethodsWe determined the effects of ODSH on lung injury produced by Pseudomonas aeruginosa (PA) infection in CF mice with the transmembrane conductance regulator gene knockout (CFTR−/−). Mice were given ODSH or normal saline intraperitoneally, followed by the determination of the bacterial load and lung injury in the airways and lung tissues. ODSH binding to HMGB1 was determined using surface plasmon resonance and in silico docking analysis of the interaction of the pentasaccharide form of ODSH with HMGB1.ResultsCF mice given 25 mg/kg i.p. of ODSH had significantly lower PA-induced lung injury compared to mice given vehicle alone. The CF mice infected with PA had decreased levels of nitric oxide (NO), increased levels of airway HMGB1 and HMGB1-impaired macrophage phagocytic function. ODSH partially attenuated the PA-induced alteration in the levels of NO and airway HMGB1 in CF mice. In addition, ODSH reversed HMGB1-impaired macrophage phagocytic function. These effects of ODSH subsequently decreased the bacterial burden in the CF lungs. In a surface plasmon resonance assay, ODSH interacted with HMGB1 with high affinity (KD = 3.89 × 10–8 M) and induced conformational changes that may decrease HMGB1’s binding to its membrane receptors, thus attenuating HMGB1-induced macrophage dysfunction.ConclusionsThe results suggest that ODSH can significantly decrease bacterial infection-induced lung injury in CF mice by decreasing both HMGB1-mediated impairment of macrophage function and the interaction of HMGB1 with membrane receptors. Thus, ODSH could represent a novel approach for treating CF and ARDS patients that have HMGB1-mediated lung injury.Graphic abstract

【 授权许可】

CC BY