Thumbnail
Access Restriction
Open

Author Ku, Sae-Kwang ♦ Baek, Moon-Chang ♦ Bae, Jong-Sup
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ANTITHYROID DRUGS ♦ INFLAMMATION ♦ INJURIES ♦ LIPOPOLYSACCHARIDES ♦ LYMPHOKINES ♦ NEOPLASMS ♦ NEUTROPHILS ♦ PHOSPHOTRANSFERASES ♦ RADIOPROTECTIVE SUBSTANCES ♦ RECEPTORS ♦ THERAPY
Abstract The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Here, methylthiouracil (MTU), an antithyroid drug, was examined for its effects on lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, human neutrophil adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells and mice. We found that post-treatment with MTU inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of human neutrophils to human endothelial cells. MTU induced potent inhibition of LPS-induced endothelial cell protein C receptor (EPCR) shedding. It also suppressed LPS-induced hyperpermeability and neutrophil migration in vivo. Furthermore, MTU suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, and the activation of nuclear factor-κB (NF-κB) and extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, post-treatment with MTU resulted in reduced LPS-induced lethal endotoxemia. These results suggest that MTU exerts anti-inflammatory effects by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. - Highlights: • MTU reduced LPS-mediated hyperpermeability in vitro and in vivo. • MTU inhibited LPS-mediated leukocyte adhesion and migration. • MTU inhibited LPS-mediated production of IL-6 and TNF-α. • MTU reduced LPS-mediated mortality and lung injury.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-11-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 288
Issue Number 3


Open content in new tab

   Open content in new tab