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

  1. Makoto Sasaki1,
  2. Sulaiman Bharwani4,
  3. Paul Jordan3,
  4. Takashi Joh5,
  5. Kenneth Manas3,
  6. April Warren1,
  7. Hirohisa Harada1,
  8. Patsy Carter1,
  9. John W. Elrod1,
  10. Michael Wolcott2,
  11. Matthew B. Grisham1 and
  12. J. Steven Alexander1
  1. 1Department of Molecular and Cellular Physiology (M.S., A.W., H.H, P.C., J.W.E., M.B.G., J.S.A.), 2Microbiology and Immunology (M.W.),3Gastroenterology (P.J., K.M.), and 4Pathology (S.B.), Louisiana State University Health Sciences Center, Shreveport, Louisiana; and5Department of Internal Medicine and Bioregulation (T.J.), Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  1. Dr. J. Steven Alexander, Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. E-mail:jalexa{at}lsuhsc.edu

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

  • 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.
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  1. Published online before print January 21, 2003, doi: 10.1124/jpet.102.044099 JPET April 1, 2003 vol. 305 no. 1 78-85
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