title: Ameliorative effect of methylthiouracil on TGFBIp-induced septic responses.
abstract: The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells (HUVECs), and functions as a mediator of experimental sepsis. Here, we investigated the anti-septic effects and underlying mechanisms of methylthiouracil (MTU), used as antithyroid drug, against TGFBIp-mediated septic responses in HUVECs and mice. The anti-inflammatory activities of MTU were determined by measuring permeability, human neutrophils adhesion and migration, and activation of pro-inflammatory proteins in TGFBIp-activated HUVECs and mice. According to the results, MTU effectively inhibited lipopolysaccharide-induced release of TGFBIp, and suppressed TGFBIp-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, MTU suppressed CLP-induced sepsis lethality and pulmonary injury. Collectively, these results indicate that MTU could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway.
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 Republic of Korea.
authors.forename: Byeongjin
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, South Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 Republic of Korea. Electronic address: baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008779:Methylthiouracil / Q000494:pharmacology*; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D018805:Sepsis / Q000503:physiopathology / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099222:betaIG-H3 Protein
chemical_list: D013956:Antithyroid Agents; D016326:Extracellular Matrix Proteins; D008779:Methylthiouracil; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein
keywords: Drug repositinging; Methylthiouracil; Sepsis; TGFBIp