Abstract
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.
Footnotes
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DOI: 10.1124/jpet.102.044099
- Abbreviations:
- IBD
- inflammatory bowel disease
- NO
- nitric oxide
- NOS
- nitric-oxide synthase
- eNOS
- endothelial nitric-oxide synthase
- iNOS
- inducible nitric-oxide synthase
- HMG
- 3-hydroxy-3-methylglutaryl
- DSS
- dextran sulfate sodium
- PBS
- phosphate-buffered saline
- DAI
- disease activity index
- EB
- Evans blue
- DMF
- N,N-dimethyl-formamide
- RT-PCR
- reverse transcription-polymerase chain reaction
- PLSD
- protected least significant difference
- MAdCAM-1
- mucosal addressin cell adhesion molecule-1
- ANOVA
- analysis of variance
- Received September 6, 2002.
- Accepted November 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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