期刊
MOLECULAR MEDICINE REPORTS
卷 13, 期 1, 页码 811-816出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2015.4574
关键词
LY294002; lipopolysaccharide; acute hepatitis; I kappa B phosphorylation
资金
- Wuhan Science and Technology, Wuhan, China [2013062301010818]
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-alpha, interleukin (IL)-6, IL-1 beta and interferon-gamma. Furthermore, LY294002 was observed to significantly inhibit I kappa B phosphorylation in LPS-injured mouse liver samples. Therefore, LY294002 may protect the liver from LPS-induced injury by inhibition of the I kappa B-nuclear factor kappa-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.
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