title: Circulating histones exacerbate inflammation in mice with acute liver failure.
abstract: Circulating histones are a newly recognized mediator implicated in various inflammatory diseases. It is likely that the release of histones, from dying hepatocytes or inflammatory leukocytes, into the circulation initiates and amplifies inflammation during the course of acute liver failure (ALF). In this study, we investigated a putative pathogenic role of circulating histones in a murine model of ALF induced by D-galactosamine (GalN) plus lipopolysaccharide (LPS). Hepatic function and histological indexes, myeloperoxidase (MPO) activity, hepatocyte apoptosis and the levels of circulating histone were measured in GalN/LPS-treated mice. GalN/LPS caused severe liver damage and a notable increase in plasma concentration of circulating histones. To further assess the role of circulating histones in our model, we administered exogenous histones and anti-histone H4 antibody. Notably, exogenous histones aggravated GalN/LPS-induced hepatotoxicity, whereas anti-histone antibody significantly protected mice. Circulating histones may serve as both a functional marker of ALF activity and as an inflammatory mediator contributing to the progression of ALF. Blockade of circulating histones shows potent protective effects, suggesting a potential therapeutic strategy for ALF.
authors.affiliation: Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, PR China.
authors.forename: Zongmei
authors.initials: Z
authors.lastname: Wen
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
authors.forename: Xiuhui
authors.initials: X
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006657:Histones / Q000097:blood*; D007249:Inflammation / Q000097:blood* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000097:blood* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D006657:Histones
keywords: ACUTE LIVER FAILURE; APOPTOSIS; CIRCULATING HISTONE; INFLAMMATION