| PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice. | |
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MedLine Citation:
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PMID: 15319270 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: In endotoxemia, lipopolysaccharide (LPS) induces a systemic inflammatory response and intravascular coagulation. Monocytes orchestrate the innate immune response to LPS by expressing a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and the procoagulant molecule, tissue factor (TF). In this study, we analyzed the role of the phosphoinositide 3-kinase (PI3K)-Akt pathway in the activation of coagulation and the innate immune response in a mouse model of endotoxemia. METHODS AND RESULTS: Wortmannin and LY294002 were used to inhibit the PI3K-Akt pathway. We found that wortmannin inhibited LPS-induced Akt phosphorylation in blood cells. Inhibition of the PI3K-Akt pathway significantly increased TF mRNA expression in blood cells, TF antigen, and thrombin-antithrombin III levels in the plasma, and fibrin deposition in the liver of endotoxemic mice. Inhibition of the PI3K-Akt pathway also strongly enhanced LPS-induced cytokine expression and the levels of soluble E-selectin in the plasma, suggesting enhanced activation of both monocytes and endothelial cells. Wortmannin treatment also increased the number of macrophages in the liver and kidney of endotoxemic mice. Finally, wortmannin and LY294002 dramatically reduced the survival time of endotoxemic mice. CONCLUSIONS: These data suggest that the PI3K-Akt pathway suppresses LPS-induced inflammation and coagulation in endotoxemic mice. |
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Authors:
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Gernot Schabbauer; Michael Tencati; Brian Pedersen; Rafal Pawlinski; Nigel Mackman |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2004-08-19 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 24 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-10-08 Completed Date: 2005-03-24 Revised Date: 2012-06-22 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1963-9 Citation Subset: IM |
Affiliation:
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Department of Immunology, The Scripps Research Institute, La Jolla, Calif 92037, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Androstadienes
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pharmacology Animals Blood Coagulation / physiology* Chemokines / metabolism, physiology Chromones / pharmacology Cytokines / metabolism, physiology Disease Models, Animal Endothelial Cells / drug effects, physiology Endothelium, Vascular / drug effects, physiology Endotoxemia / metabolism*, mortality Humans Inflammation / metabolism Kidney / pathology Lipopolysaccharides / immunology Liver / pathology Macrophage Activation / physiology Mice Mice, Inbred C57BL Monocytes / physiology Morpholines / pharmacology Phosphatidylinositol 3-Kinases / antagonists & inhibitors, metabolism* Protein-Serine-Threonine Kinases / antagonists & inhibitors, metabolism* Proto-Oncogene Proteins / antagonists & inhibitors, metabolism* Proto-Oncogene Proteins c-akt Signal Transduction / physiology |
| Grant Support | |
ID/Acronym/Agency:
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HL48872/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Androstadienes; 0/Chemokines; 0/Chromones; 0/Cytokines; 0/Lipopolysaccharides; 0/Morpholines; 0/Proto-Oncogene Proteins; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 19545-26-7/wortmannin; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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