期刊
FASEB JOURNAL
卷 36, 期 11, 页码 -出版社
WILEY
DOI: 10.1096/fj.202200228RRRRR
关键词
acute lung injury; heparin-binding protein (HBP); infection; transforming growth factor-beta receptor type 2 (TGF-beta-R2); vascular permeability
资金
- Clinical Research Center of Critical Care Medicine, Shenyang [20-204-4-41]
- National 14th Five-Year Key Research and Development Plan [2021YFC2500805]
- National Natural Science Foundation of China [82102266]
- Clinical Research Center of Critical Care Medicine, Liaoning province [1586657730871]
Heparin-binding protein (HBP), secreted by neutrophils, plays a role in the pathophysiology of sepsis. Our studies showed that HBP binds to transforming growth factor-beta receptor type 2 (TGF-beta-R2) and triggers acute lung injury and vascular leakage through the TGF-beta/SMAD2/3 signaling pathway. The role of HBP and TGF-beta-R2 in HBP-related acute lung injury at the blood-gas barrier was also defined.
Heparin-binding protein (HBP), as a granule protein secreted by polymorphonuclear neutrophils, participates in the pathophysiological process of sepsis. It has been reported that HBP is a biomarker of sepsis related to the severity of septic shock and organ dysfunction. HBP binds to vascular endothelial cells as a primary target site. However, it is still unclear whether HBP-binding protein receptors exist on the surface of endothelial cells. The effect of HBP on vascular permeability in sepsis and its mechanism needs to be explored. We conducted in vivo and in vitro studies and demonstrated that HBP binds to transforming growth factor-beta receptor type 2 (TGF-beta-R2) as a ligand. Glutathione S-transferase pulldown analysis revealed that HBP mainly interacts with the extracellular domain of TGF-beta-R2. HBP induces acute lung injury and vascular leakage via activation of the TGF-beta/SMAD2/3 signaling pathway. A permeability assay suggested that TGF-beta-R2 is necessary for HBP-induced increased permeability. We also defined the role of HBP and its potential membrane receptor TGF-beta-R2 in the blood-gas barrier in the pathogenesis of HBP-related acute lung injury.
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