Reference - Detail
|Author||Hirano K, Shimizu Y, Nakayama Y, Minemura M, Yasumura S, Sugiyama T.|
|Title||Overexpression of granulocyte-macrophage colony-stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes.|
BACKGROUND/AIMS:We examined whether antigen-nonspecific accumulation of dendritic cells (DCs) and macrophages in the liver by the overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) could prime severe liver injury after LPS injection.
METHODS:We injected a recombinant adenovirus encoding GM-CSF intravenously (AdGM), and LPS was administered 7 days later. Liver histology, serum alanine aminotransferase (ALT) levels and apoptosis of hepatocytes were examined.
RESULTS:Liver histology of the AdGM-primed mice showed marked infiltrates of mononuclear cells (DCs and macrophages) without granuloma formation on day 7. Expression of toll-like receptor-4 on intrahepatic mononuclear cells isolated from AdGM-primed mice was up-regulated. After LPS injection, serum ALT levels in AdGM-primed mice reached about 6000 IU/l at 12 h, and all those mice died within 24 h. Hemorrhagic liver injury with massive apoptosis of hepatocytes was histologically recognized. When AdGM and LPS were injected in FasL-deficient C57BL/6J-gld/gld mice, serum ALT levels were not elevated by the pretreatment with a neutralizing anti-TNF-alpha antibody.
CONCLUSIONS:Our present study provides a new model of severe liver injury, in which antigen-nonspecific accumulation of DCs and macrophages in the liver by overexpressing GM-CSF enhances the susceptibility to LPS, leading to hemorrhagic liver injury with massive hepatocyte apoptosis after LPS injection.
|MeSH||Adenoviridae / genetics Animals Apoptosis / drug effects* CD11c Antigen / analysis Dendritic Cells / physiology Female Granulocyte-Macrophage Colony-Stimulating Factor / genetics Granulocyte-Macrophage Colony-Stimulating Factor / physiology* Hepatocytes / drug effects* Hepatocytes / pathology Interferon-gamma / blood Lipopolysaccharides / toxicity* Liver / metabolism* Macrophages / physiology Mice Mice, Inbred C57BL Toll-Like Receptor 2 / analysis Toll-Like Receptor 4 / analysis Tumor Necrosis Factor-alpha / physiology fas Receptor / physiology|
|WOS Category||GASTROENTEROLOGY & HEPATOLOGY|
|DNA material||pAxCAmGM-CSF (RDB1418)|