Antiseptic effects of dabrafenib on TGFBIp-induced septic responses

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>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 <I>in vivo</I>. 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Transforming growth factor β induced protein (TGFBIp) is an important extracellular mediator of sepsis. </LI> <LI> DAB inhibited LPS-induced secretion of TGFBIp. </LI> <LI> DAB inhibited TGFBIp-mediated hyperpermeability. </LI> <LI> DAB inhibited TGFBIp-mediated septic response. </LI> <LI> DAB reduced TGFBIp-induced septic mortality. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>