Abstract
LXR is another member of the superfamily of nuclear hormone receptors that heterodimerizes with RXR and regulates the intracellular levels of cholesterol through gene induction of enzymes and proteins involved in the cholesterol metabolism and transport. LXR ligands inhibit the gene expression of proinflammatory mediators in immunostimulated macrophages; in vivo studies have shown that activation of LXR reduces the inflammatory response in a murine model of contact dermatitis and atherosclerosis. No reports have addressed a role for LXRs in pathophysiology of intestinal ischemia. The aim of this study was to investigate the effects of T0901317, a potent LXR ligand, in a mouse model of SAO shock, which was induced by clamping the superior mesenteric artery and the celiac trunk, resulting in a total occlusion of these arteries for 30 min. After this period of occlusion, the clamps were removed. Mice were killed at 60 min after reperfusion. This study provides the evidence that T0901317, LXR agonist, modulates: the development of SAO shock; the infiltration of the tissue with PMNs; the expression of TNF-alpha and IL-1beta; the nitration of tyrosine residues; NF-kappaB expression; the MAPK phosphorylation (ERK, JNK, and p38); FasL; apoptosis; Bax and Bcl-2 expression; and the degree of tissue injury caused by SAO shock. Our results imply that LXR agonists may be useful in the therapy of inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cholesterol / immunology
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Cholesterol / metabolism
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Hydrocarbons, Fluorinated / pharmacology*
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Inflammation / drug therapy
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / immunology
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Intestine, Small / blood supply*
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Intestine, Small / immunology
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Intestine, Small / metabolism
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Liver X Receptors
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / immunology
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Mice
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NF-kappa B / biosynthesis
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NF-kappa B / immunology
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Orphan Nuclear Receptors / agonists*
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Orphan Nuclear Receptors / immunology
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Orphan Nuclear Receptors / metabolism
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Reperfusion Injury / drug therapy
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Reperfusion Injury / immunology*
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Reperfusion Injury / metabolism
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Reperfusion Injury / pathology
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Retinoid X Receptors / immunology
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Retinoid X Receptors / metabolism
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Splanchnic Circulation / drug effects
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Splanchnic Circulation / immunology
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Sulfonamides / pharmacology*
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
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bcl-2-Associated X Protein / biosynthesis
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bcl-2-Associated X Protein / immunology
Substances
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Bax protein, mouse
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Hydrocarbons, Fluorinated
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Inflammation Mediators
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Interleukin-1beta
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Liver X Receptors
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NF-kappa B
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Orphan Nuclear Receptors
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Retinoid X Receptors
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Sulfonamides
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T0901317
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Tumor Necrosis Factor-alpha
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bcl-2-Associated X Protein
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Cholesterol