title: Inhibition of UII/UTR system relieves acute inflammation of liver through preventing activation of NF-κB pathway in ALF mice.
abstract: Urotensin II (UII) is implicated in immune inflammatory diseases through its specific high-affinity UT receptor (UTR). Enhanced expression of UII/UTR was recently demonstrated in the liver with acute liver failure (ALF). Here, we analysed the relationship between UII/UTR expression and ALF in lipopolysaccharide (LPS)/D-galactosamine (GalN)-challenged mice. Thereafter, we investigated the effects produced by the inhibition of UII/UTR system using urantide, a special antagonist of UTR, and the potential molecular mechanisms involved in ALF. Urantide was administered to mice treated with LPS/GalN. Expression of UII/UTR, releases of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interferon-γ (IFN-γ), and activation of nuclear factor κB (NF-κB) signaling pathway were assessed in the lethal ALF with or without urantide pretreatment. We found that LPS/GalN-challenged mice showed high mortality and marked hepatic inflammatory infiltration and cell apoptosis as well as a significant increase of UII/UTR expression. Urantide pretreatment protected against the injury in liver following downregulation of UII/UTR expression. A close relationship between the acutely flamed hepatic injury and UII/UTR expression was observed. In addition, urantide prevented the increases of proinflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and activation of NF-κB signaling pathway induced by LPS/GalN in mice. Thus, we conclude that UII/UTR system plays a role in LPS/GalN-induced ALF. Urantide has a protective effect on the acutely inflamed injury of liver in part through preventing releases of proinflammatory cytokines and activation of NF-κB pathway.
authors.affiliation: Department of Hepatology, Songjiang Hospital Affiliated to the First People's Hospital Shanghai Jiaotong University, Shanghai, China.
authors.forename: Dong-yu
authors.initials: DY
authors.lastname: Liang
authors.forename: Liang-ming
authors.initials: LM
authors.lastname: Liu
authors.forename: Chang-gen
authors.initials: CG
authors.lastname: Ye
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Fang-ping
authors.initials: FP
authors.lastname: Yu
authors.forename: De-yong
authors.initials: DY
authors.lastname: Gao
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: Wang
authors.forename: Zhi-wen
authors.initials: ZW
authors.lastname: Yang
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Wang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005688:Galactosamine; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014579:Urotensins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C512325:urotensin II receptor, mouse; D005688:Galactosamine; C029677:urotensin II