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Research ArticleArticle

Ethanol-Induced Barrier Dysfunction and Its Prevention by Growth Factors in Human Intestinal Monolayers: Evidence for Oxidative and Cytoskeletal Mechanisms

A. Banan, S. Choudhary, Y. Zhang, J. Z. Fields and A. Keshavarzian
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1075-1085;
A. Banan
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S. Choudhary
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Y. Zhang
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J. Z. Fields
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A. Keshavarzian
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Abstract

Exposure of intestinal mucosa to ethanol (EtOH) disrupts barrier function and growth factors [epidermal growth factor (EGF) and transforming growth factor-α (TGF-α)] are protective, but the mechanisms remain obscure. Accordingly, we sought to determine whether the molecular mechanism of EtOH-induced intestinal barrier dysfunction involves oxidative stress and disassembly of microtubules and whether the mechanism of protection by EGF or TGF-α involves prevention of these alterations. To this end, human colonic (Caco-2) monolayers were exposed to 0 to 15% EtOH with or without pretreatment with EGF or TGF-α (10 ng/ml) or with oxidative or cytoskeletal modulators. Effects on cell viability, barrier function, tubulin (microtubules), and oxidative stress were then determined. Cells were also processed for immunoblots of polymerized tubulin (S2; index of stability) and the monomeric tubulin (S1; index of disruption). EtOH dose-dependently decreased the stable S2 polymerized tubulin and concomitantly increased measures of oxidative stress, including oxidation and nitration of tubulin, fluorescence of dichlorofluorescein, and inducible nitric oxide synthase activity. EtOH also dose-dependently disrupted barrier function and extensively damaged microtubules, and these effects were prevented by pretreatment with antioxidant scavengers:l-cysteine, superoxide dismutase, andl-N6-1-iminoethyl-lysine (an inducible nitric oxide synthase inhibitor). In monolayers exposed to EtOH, pretreatment with EGF or TGF-α prevented the oxidation and nitration of tubulin, increases in the levels of the unstable S1 tubulin, disruption of microtubules, and barrier dysfunction. A microtubule stabilizer (paclitaxel,Taxol) mimicked, in part, the effects of EGF and TGF-α, whereas a microtubule disruptive drug (colchicine) prevented the protective effects of these growth factors. We concluded that mucosal barrier dysfunction induced by EtOH involves oxidative stress, which causes the disassembly of the microtubule cytoskeleton. Protection by EGF and TGF-α involves the prevention of these EtOH-induced alterations in microtubules.

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}rsh.net

  • ↵1 This work was supported in part by a grant from Otsuka America Pharmaceutical Company.

  • Abbreviations:
    EtOH
    ethanol
    NOS
    nitric oxide synthase
    iNOS
    inducible nitric oxide synthase
    GI
    gastrointestinal
    DCF
    dichlorofluorescein
    FSA
    fluorescein sulfonic acid
    DMEM
    Dulbecco's modified Eagle's medium
    EGF
    epidermal growth factor
    TGF-α
    transforming growth factor-α
    DNP
    dinitrophenylhydrazone
    SOD
    superoxide dismutase
    l-NIL
    l-N6-1-iminoethyl-lysine
    EGFR
    epidermal growth factor receptor
    PAGE
    polyacrylamide gel electrophoresis
    PBS-T
    PBS/Tween 20
    • Received May 11, 1999.
    • Accepted August 13, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Ethanol-Induced Barrier Dysfunction and Its Prevention by Growth Factors in Human Intestinal Monolayers: Evidence for Oxidative and Cytoskeletal Mechanisms

A. Banan, S. Choudhary, Y. Zhang, J. Z. Fields and A. Keshavarzian
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1075-1085;

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Research ArticleArticle

Ethanol-Induced Barrier Dysfunction and Its Prevention by Growth Factors in Human Intestinal Monolayers: Evidence for Oxidative and Cytoskeletal Mechanisms

A. Banan, S. Choudhary, Y. Zhang, J. Z. Fields and A. Keshavarzian
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1075-1085;
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