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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 21, 2003; DOI: 10.1124/jpet.102.044099

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Vol. 305, Issue 1, 78-85, April 2003

The 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Pravastatin Reduces Disease Activity and Inflammation in Dextran-Sulfate Induced Colitis

Makoto Sasaki, Sulaiman Bharwani, Paul Jordan, Takashi Joh, Kenneth Manas, April Warren, Hirohisa Harada, Patsy Carter, John W. Elrod, Michael Wolcott, Matthew B. Grisham and J. Steven Alexander

Department of Molecular and Cellular Physiology (M.S., A.W., H.H, P.C., J.W.E., M.B.G., J.S.A.), Microbiology and Immunology (M.W.), Gastroenterology (P.J., K.M.), and Pathology (S.B.), Louisiana State University Health Sciences Center, Shreveport, Louisiana; and Department of Internal Medicine and Bioregulation (T.J.), Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.

0022-3565/03/3051-0078$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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