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Research ArticleTOXICOLOGY

Nitric Oxide and Its Metabolites Mediate Ethanol-Induced Microtubule Disruption and Intestinal Barrier Dysfunction

Ali Banan, Jeremy Z. Fields, Heather Decker, Yang Zhang and Ali Keshavarzian
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 997-1008;
Ali Banan
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Jeremy Z. Fields
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Heather Decker
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Yang Zhang
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Ali Keshavarzian
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Abstract

Loss of gastrointestinal (GI) barrier integrity has been implicated in a wide range of inflammatory illnesses, including alcoholic cirrhosis. Using monolayers of Caco-2 (intestinal) cells as a model, we showed that the ability of ethanol (EtOH) to disrupt intestinal barrier integrity depends on damage to the microtubule (MT) cytoskeleton, especially oxidative injury. One drug that prevented both the MT damage and barrier disruption wasl-N6-1-iminoethyl-lysine, a selective inhibitor of the inducible form of nitric-oxide synthase (iNOS). Because of this finding and because overproduction of nitric oxide (NO) and generation of peroxynitrite (ONOO−) have been proposed to be responsible for mucosal injury in other GI disorders, we sought to determine whether NO overproduction and ONOO− formation mediates EtOH-induced MT damage and loss of intestinal barrier function. To this end, Caco-2 monolayers were exposed to EtOH or to authentic ONOO− or ONOO− generators with or without pretreatment with iNOS inhibitors or antioxidants. We found that EtOH caused 1) iNOS activation, 2) NO overproduction, 3) increases in oxidative stress and superoxide anion production (superoxide dismutase quenchable fluorescence of dichlorofluorescein), 4) nitration and oxidation of tubulin (immunoblotting), 5) decreased levels of stable polymerized tubulin, and 6) increased levels of disassembled tubulin. EtOH also 7) extensively damaged the MT cytoskeleton and 8) disrupted barrier function. Authentic ONOO− or ONOO− donors had similar effects. Pretreatment with a selective iNOS inhibitor,l-N6-1-iminoethyl-lysine, or with antioxidants (ONOO− scavengers urate orl-cysteine; superoxide anion scavenger superoxide dismutase) attenuated damage due to EtOH or to ONOO−generators. We conclude that EtOH-induced MT damage and intestinal barrier dysfunction require iNOS activation followed by NO overproduction and ONOO− formation. These findings provide a rationale for the development of novel therapeutic agents for alcohol-induced GI disorders that inhibit this mechanism.

Footnotes

  • Send reprint requests to: Ali Banan, Ph.D., Rush University Medical Center, Division of Digestive Diseases, 1725 W. Harrison, Suite 206, Chicago, IL 60612. E-mail: ali_banan{at}rush.edu

  • ↵1 This work was supported in part by a grant from Rush University Medical Center. Portions of this work will be presented in the abstract form at the annual meeting of the American Gastroenterological Association in San Diego, CA, 2000.

  • Abbreviations:
    GI
    gastrointestinal
    MT
    microtubule
    l-NIL
    l-N6-1-iminoethyl-lysine
    NO
    nitric oxide
    NOS
    nitric-oxide synthase
    iNOS
    inducible NOS
    EtOH
    ethanol
    EGF
    epidermal growth factor
    FSA
    fluorescein sulfonic acid
    SOD
    superoxide dismutase
    iSOD
    heat-inactivated SOD
    LSCM
    laser scanning confocal microscopy
    l-NNA
    NG-nitro-l-arginine
    HRP
    horseradish peroxidase
    l-Arg
    l-arginine
    l-NMMA
    NG-monomethyl-l-arginine
    DNP
    2,4-dinitrophenylhydrazine
    DCF
    dichlorofluorescein
    DCFD
    2′,7′-dichlorofluorescein diacetate
    X
    xanthine
    XO
    xanthine oxidase
    SIN-1
    1,3-morpholinosydnonymine
    SNAP
    S-nitroso-N-acetyl penicillamine
    D-PBS
    Dulbecco's PBS
    • Received February 9, 2000.
    • Accepted May 31, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleTOXICOLOGY

Nitric Oxide and Its Metabolites Mediate Ethanol-Induced Microtubule Disruption and Intestinal Barrier Dysfunction

Ali Banan, Jeremy Z. Fields, Heather Decker, Yang Zhang and Ali Keshavarzian
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 997-1008;

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Research ArticleTOXICOLOGY

Nitric Oxide and Its Metabolites Mediate Ethanol-Induced Microtubule Disruption and Intestinal Barrier Dysfunction

Ali Banan, Jeremy Z. Fields, Heather Decker, Yang Zhang and Ali Keshavarzian
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 997-1008;
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