title: LY294002 prevents lipopolysaccharide‑induced hepatitis in a murine model by suppressing IκB phosphorylation.
abstract: Although fulminant hepatitis represents a ubiquitous human health problem, there is a lack of effective therapeutic strategies that have few side‑effects and the precise mechanisms underlying fulminant hepatitis are not fully understood. Phosphoinositide 3‑kinase (PI3K) is a pivotal kinase known to regulate inflammatory responses in hepatic diseases. Although previous research indicates that PI3K is involved in cardiac diseases, including myocardial infarction, it currently remains unclear whether the inhibition of PI3K is essential for ameliorating the severity of lipopolysaccharide (LPS)‑induced hepatitis. The aim of the present study was to investigate whether pharmacological blockade of PI3K ameliorates the development of LPS‑induced murine acute hepatic injury. A murine model of LPS‑induced acute hepatic injury was used to investigate the therapeutic effect of the pan‑PI3K inhibitor, LY294002 on murine fulminant hepatitis and to investigate potential underlying mechanisms. The current report presents the in vivo role of LY294002 in protecting the mice from fulminant hepatitis. LY294002 was observed to exert significant protective effects on the liver by reducing the activities of alanine aminotransferase and aspartate aminotransferase, as well as by improving the histological architecture of the liver. In LPS‑induced hepatitis, treatment with LY294002 clearly inhibited intrahepatic synthesis of various disease‑relevant proinflammatory cytokines, including tumor necrosis factor‑α, interleukin (IL)‑6, IL‑1β and interferon‑γ. Furthermore, LY294002 was observed to significantly inhibit IκB phosphorylation in LPS‑injured mouse liver samples. Therefore, LY294002 may protect the liver from LPS‑induced injury by inhibition of the IκB‑nuclear factor κ‑light‑chain‑enhancer of activated B cell dependent signaling pathway. Thus, the current report provides evidence that LY294002 exerts potent effects against LPS‑induced hepatic injury, indicating its potential therapeutic value for the treatment of acute hepatitis.
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Zhize
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D002867:Chromones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D020672:I-kappa B Proteins / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D002867:Chromones; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one