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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acute Mechanism of Medium Chain Fatty Acid-Induced Enhancement of Airway Epithelial Permeability

Carolyn B. Coyne, Carla M. P. Ribeiro, Richard C. Boucher and Larry G. Johnson
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 440-450; DOI: https://doi.org/10.1124/jpet.102.047654
Carolyn B. Coyne
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Carla M. P. Ribeiro
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Richard C. Boucher
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Larry G. Johnson
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Abstract

The localization of viral receptors to the basolateral surface of airway epithelia is an obstacle to the effectiveness of luminal viral-mediated gene transfer to the lung. The tight junction (TJ) serves as a rate-limiting barrier to the penetration of viral vectors. We have previously identified the sodium salt of the medium chain fatty acid (MCFA) capric acid (C10) as an agent that can enhance the ability of adenoviral vectors to transduce well differentiated (WD) primary human airway epithelial (HAE) cells. Previous studies have suggested that intracellular calcium (Cai2+) levels may play a central role in the long-term C10-mediated increases in junctional permeability. In this study, we investigated the effects of C10 and lauric acid (C12) on Cai2+ in WD primary HAE cells and determined whether these effects were necessary for the acute MCFA-induced reduction in transepithelial resistance (RT) and increased permeability. In addition, we characterized the effects of C10 and C12 on components localized to the TJ, including ZO-1, junctional adhesion molecule (JAM), and the claudin family of transmembrane proteins. In addition to rapidly decreasing RT, C10 and C12 increased cellular and paracellular permeability. C10 induced a rapid, sustained increase in Cai2+. However, buffering Cai2+ did not block the effects of C10 onRT. Both C10 and C12 caused reorganization of claudins-1, -4, JAM, and β-catenin, but not ZO-1. These data suggest that C10 and C12 exert their acute effects on airway TJs via a Ca2+-independent mechanism of action and may alter junctional permeability via direct effects on the claudin family of TJ proteins.

Footnotes

  • This work was supported by Grants HL58342 and HL51818 from the National Heart, Lung, and Blood Institute.

  • DOI: 10.1124/jpet.102.047654

  • Abbreviations:
    TJ
    tight junction
    MCFA
    medium chain fatty acid
    C10
    capric acid
    C12
    lauric acid
    Cai2+
    intracellular calcium
    PLC
    phospholipase C
    HAE
    human airway epithelial
    RT
    transepithelial resistance
    JAM
    junctional adhesion molecule
    BAPTA-AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetomethyl ester
    Ad
    adenovirus
    PBS
    phosphate-buffered saline
    HBR
    HEPES-buffered Ringer
    TR
    Texas Red
    C8
    caprylic acid
    βgal
    β-galactosidase
    CAR
    coxsackie virus B and Ad2/5 receptor
    ER
    endoplasmic reticulum
    U73122
    1-[6-[(17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl-1H-pyrrole-2,5-dione
    48/80
    condensation product ofN-methyl-p-methoxyphenylethylamine with formaldehyde
    W7
    1-(5-chloronapthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride
    KN62
    (S)-5-isoquinolinesulfonic acid
    H7
    1-(5-isoquinolinesulfonyl)-2-methylpiperazine
    AM
    acetoxymethyl ester
    • Received December 3, 2002.
    • Accepted February 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acute Mechanism of Medium Chain Fatty Acid-Induced Enhancement of Airway Epithelial Permeability

Carolyn B. Coyne, Carla M. P. Ribeiro, Richard C. Boucher and Larry G. Johnson
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 440-450; DOI: https://doi.org/10.1124/jpet.102.047654

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acute Mechanism of Medium Chain Fatty Acid-Induced Enhancement of Airway Epithelial Permeability

Carolyn B. Coyne, Carla M. P. Ribeiro, Richard C. Boucher and Larry G. Johnson
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 440-450; DOI: https://doi.org/10.1124/jpet.102.047654
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