Antiseptic effects of dabrafenib on TGFBIp-induced septic responses. (25th December 2017)

• Record Type: Journal Article
• Authors: Lee, In-Chul; Bae, Jong-Sup
• Is Part Of: Chemico-biological interactions. Volume 278(2017)
• Page Start: 92
• Page End: 100
• Publication Date: 2017-12-25
• Subjects: Dabrafenib -- TGFBIp -- Inflammation -- Sepsis; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2017.10.016
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Transforming growth factor-β-induced protein (TGFBIp), an extracellular protein, is expressed on several cell types in response to TGF-β stimulation. Human umbilical vein endothelial cell (HUVEC)-derived TGFBIp functions as a mediator of sepsis. Screening of bioactive compound libraries is an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases (drug repositioning). Dabrafenib (DAB), a B-Raf inhibitor, was initially used for treating metastatic melanoma. The present study determined whether DAB modulated TGFBIp-mediated septic responses in HUVECs and in mice. Antiseptic functions of DAB were examined by measuring permeability, leukocyte adhesion and migration, and proinflammatory protein activation in TGFBIp-stimulated HUVECs and mice. In addition, beneficial effects of DAB on survival rate were examined using a mouse model of sepsis. We found that DAB inhibited TGFBIp-induced vascular barrier disruption, cell adhesion molecule (CAM) expression, and neutrophil adhesion/transendothelial migration toward human endothelial cells. DAB also suppressed TGFBIp-induced hyperpermeability and leukocyte migration in vivo . These results suggest that DAB exerts anti-inflammatory effects by inhibiting hyperpermeability, CAM expression, and leukocyte adhesion and migration, indicating its utility for treating vascular inflammatory diseases. Graphical abstract: Highlights: Transforming growth factor β induced protein (TGFBIp) is an important extracellular mediator of sepsis. DAB inhibited LPS-induced secretion of TGFBIp. DAB inhibited TGFBIp-mediated hyperpermeability. DAB inhibited TGFBIp-mediated septic response. DAB reduced TGFBIp-induced septic mortality.