Methylthiouracil, a new treatment option for sepsis.
The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as an attractive therapeutic strategies in the management of severe sepsis or septic shock. Here, we examined the effects of methylthiouracil (MTU), used as antithyroid drug, by monitoring the effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1, and on the modulation of HMGB1-mediated inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, leukocyte adhesion and migration, and the activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice. MTU inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. MTU also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with MTU reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury. Our results indicate that MTUs could be candidate therapeutic agents for various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.
['Kwak|Soyoung|S|', 'Ku|Sae-Kwang|SK|', 'Kang|Hyejin|H|', 'Baek|Moon-Chang|MC|', 'Bae|Jong-Sup|JS|']
D000818:Animals D000893:Anti-Inflammatory Agents D002465:Cell Movement D004195:Disease Models, Animal D024243:HMGB1 Protein D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D007249:Inflammation D007962:Leukocytes D008070:Lipopolysaccharides D008297:Male D008779:Methylthiouracil D051379:Mice D008810:Mice, Inbred C57BL D018805:Sepsis D015398:Signal Transduction
Methylthiouracil Sepsis HMGB1 Drug repositioning