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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of Ozone Treatment on Airway Reactivity and Epithelium-Derived Relaxing Factor in Guinea Pigs

Jeffrey S. Fedan, Lyndell L. Millecchia, Richard A. Johnston, Appavoo Rengasamy, Ann Hubbs, Richard D. Dey, Long-Xing Yuan, David Watson, W. Travis Goldsmith, Jeffrey S. Reynolds, Larry Orsini, Juanita Dortch-Carnes, Deborah Cutler and David G. Frazer
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 724-734;
Jeffrey S. Fedan
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Lyndell L. Millecchia
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Richard A. Johnston
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Appavoo Rengasamy
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Ann Hubbs
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Richard D. Dey
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Long-Xing Yuan
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David Watson
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W. Travis Goldsmith
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Jeffrey S. Reynolds
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Larry Orsini
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Juanita Dortch-Carnes
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Deborah Cutler
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David G. Frazer
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Abstract

Ozone (O3) is toxic to respiratory epithelium and causes airway inflammation and hyperreactivity. To evaluate the role of the epithelium in the development of hyperreactivity, we examined in guinea pigs the effects of inhaled O3 (3 ppm for 1 h; 0–24 h after exposure) on 1) reactivity to inhaled methacholine (MCh), 2) reactivity of the isolated, perfused trachea (IPT) to MCh, 3) epithelium-derived relaxing factor (EpDRF)-mediated relaxations of IPT induced by mucosal hyperosmolar solutions, 4) neurogenic contraction and relaxation responses, 5) transepithelial potential difference, and 6) microscopic analysis of nitrotyrosine immunofluorescence, substance P fiber density, and tracheal morphology. At 0 h, O3caused hyperreactivity to inhaled MCh and mucosally but not serosally applied MCh in IPT (only in the presence of the epithelium) and a decrease in transepithelial potential difference. Inhibition of EpDRF-induced relaxation responses occurred at 2 h. All of these changes returned to control by 12 to 18 h. O3 had no effect on neurogenic responses. Nitrotyrosine immunofluorescence appeared in the trachea at 0 h in detached epithelial cell ghosts and in intrapulmonary airways by 6 h. Substance P fiber density was elevated in smooth muscle at 0 and 18 h but not in epithelium or lamina propria of intrapulmonary and extrapulmonary bronchi. Loss of cilia and mucosubstances in the mucosa occurred at 0 h; the epithelium became markedly attenuated over 12 to 24 h. A reversible increase in epithelial permeability and a decrease in EpDRF production may contribute to O3-induced hyperreactivity to MCh.

Footnotes

  • Send reprint requests to: Dr. Jeffrey S. Fedan, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., Morgantown, WV 26505. E-mail:jsf2{at}cdc.gov

  • ↵1 Mention of a brand name does not constitute product endorsement.

  • ↵2 The IL/EL maximum response ratio is an index of the modulatory effect of the epithelium on the maximum contractile responses (Fedan and Frazer, 1992). The ratio is unity in the absence of epithelium and less than unity in the presence of the epithelium. The greater the inhibitory effect of the epithelium, the smaller is the value of the ratio.

  • Abbreviations:
    MCh
    methacholine
    EpDRF
    epithelium-derived relaxing factor
    MKH
    modified Krebs-Henseleit
    PMN
    polymorphonuclear leukocyte
    IL
    intraluminal
    EL
    extraluminal
    VT
    transepithelial potential difference
    EFS
    electric field stimulation
    • Received September 27, 1999.
    • Accepted February 18, 2000.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of Ozone Treatment on Airway Reactivity and Epithelium-Derived Relaxing Factor in Guinea Pigs

Jeffrey S. Fedan, Lyndell L. Millecchia, Richard A. Johnston, Appavoo Rengasamy, Ann Hubbs, Richard D. Dey, Long-Xing Yuan, David Watson, W. Travis Goldsmith, Jeffrey S. Reynolds, Larry Orsini, Juanita Dortch-Carnes, Deborah Cutler and David G. Frazer
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 724-734;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of Ozone Treatment on Airway Reactivity and Epithelium-Derived Relaxing Factor in Guinea Pigs

Jeffrey S. Fedan, Lyndell L. Millecchia, Richard A. Johnston, Appavoo Rengasamy, Ann Hubbs, Richard D. Dey, Long-Xing Yuan, David Watson, W. Travis Goldsmith, Jeffrey S. Reynolds, Larry Orsini, Juanita Dortch-Carnes, Deborah Cutler and David G. Frazer
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 724-734;
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