| TNF-alpha induces thromboxane receptor signaling-dependent microcirculatory dysfunction in mouse liver. | |
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MedLine Citation:
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PMID: 18800000 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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TNF-alpha is a critical mediator of hepatic microcirculatory dysfunction during endotoxemia. The present study was to investigate the role of thromboxane A2 (TXA2) and the biological significance of thromboxane prostanoid (TP) receptor signaling in TNF-alpha-mediated hepatic microcirculatory dysfunction in male C57Bl/6 mice. The number of leukocytes adhering to the endothelial cells of the hepatic microvessels (the portal venules, sinusoids, and central venules) and the percentage of nonperfused sinusoids were determined using in vivo fluorescence microscopy. FR167653, an inhibitor of TNF-alpha, was administered 0 and 2 h after LPS injection. A TXA2 synthase inhibitor, OKY-046, was administered 30 min before TNF-alpha injection. Thromboxane prostanoid receptor knockout mice were used to investigate whether TNF-alpha-induced hepatic microcirculatory dysfunction is mediated by endogenously produced TXA2. FR167653 reduced LPS-induced leukocyte adhesion (50%-80%) and the percentage of nonperfused sinusoids (55%). The leukocyte adhesion was increased in the portal venules (8-fold), sinusoids (51-fold), and central venules (73-fold) in TNF-alpha-treated mice, accompanied with an increase in sinusoidal perfusion deficits (8-fold). Alanine aminotransferase levels rose as the adhesion of leukocytes increased. OKY-046 administration before TNF-alpha administration reduced leukocyte adhesion (41%-49% decrease) and sinusoid perfusion deficits (34% decrease). In TP receptor knockout mice, the number of adhering leukocytes, the percentage of nonperfused sinusoids, and alanine aminotransferase levels were lower (by 43%-56%, 41%, and 29%, respectively) than in wild-type counterparts. The results suggest that TP receptor signaling may promote hepatic microcirculatory dysfunction elicited by TNF-alpha. Blockade of TNF-alpha generation and TP receptor signaling may be a good strategy for managing endotoxin-induced hepatic injury. |
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Authors:
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Hiroyuki Katagiri; Yoshiya Ito; Sohei Ito; Takahiko Murata; Sugimoto Yukihiko; Shuh Narumiya; Masahiko Watanabe; Masataka Majima |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Shock (Augusta, Ga.) Volume: 30 ISSN: 1540-0514 ISO Abbreviation: Shock Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-09-18 Completed Date: 2008-11-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421564 Medline TA: Shock Country: United States |
Other Details:
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Languages: eng Pagination: 463-7 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Adhesion Leukocytes / cytology Liver / metabolism* Male Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Microcirculation* Receptors, Thromboxane / metabolism* Recombinant Proteins / chemistry Sepsis / metabolism* Signal Transduction Tumor Necrosis Factor-alpha / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Thromboxane; 0/Recombinant Proteins; 0/Tumor Necrosis Factor-alpha |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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