Lee In-Chul, Bae Jong-Sup
Department of Cosmetic Science and Technology, Seowon University, Cheongju 28674, Republic of Korea.
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.
Chem Biol Interact. 2017 Dec 25;278:92-100. doi: 10.1016/j.cbi.2017.10.016. Epub 2017 Oct 14.
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.
转化生长因子-β诱导蛋白（TGFBIp）是一种细胞外蛋白，在多种细胞类型中响应TGF-β刺激而表达。人脐静脉内皮细胞（HUVEC）衍生的TGFBIp作为脓毒症的介质发挥作用。筛选生物活性化合物库是重新定位FDA批准药物或发现人类疾病新疗法（药物重新定位）的有效方法。达拉非尼（DAB）是一种B-Raf抑制剂，最初用于治疗转移性黑色素瘤。本研究确定了DAB是否调节HUVEC和小鼠中TGFBIp介导的脓毒症反应。通过测量TGFBIp刺激的HUVEC和小鼠的通透性、白细胞粘附和迁移以及促炎蛋白激活来检查DAB的抗菌功能。此外，使用脓毒症小鼠模型检查了DAB对存活率的有益影响。我们发现DAB抑制TGFBIp诱导的血管屏障破坏、细胞粘附分子（CAM）表达以及中性粒细胞对人内皮细胞的粘附/跨内皮迁移。DAB还在体内抑制TGFBIp诱导的高通透性和白细胞迁移。这些结果表明，DAB通过抑制高通透性、CAM表达以及白细胞粘附和迁移发挥抗炎作用，表明其在治疗血管炎性疾病方面的效用。
