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ToxSci Advance Access published online on October 30, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp268
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Airway Trefoil Factor Expression during Naphthalene Injury and Repair

Melanie A. Greeley*, Laura S. Van Winkle*,{dagger}, Patricia C. Edwards{dagger} and Charles G. Plopper*

* Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis 95616 {dagger} Center for Health and the Environment, Old Davis Road, University of California, Davis 956162

Corresponding Author: Laura S. Van Winkle, Ph.D. DABT, Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, 1 Shields Avenue, Davis, CA 95616, Voice: (530) 754-7547, Fax: (530) 752-5300, Email: lsvanwinkle{at}ucdavis.edu

Received August 12, 2009; revision received October 16, 2009; accepted October 20, 2009


  Abstract

While the role of trefoil factors (TFF) in the maintenance of epithelial integrity in the gastrointestinal tract is well known, their involvement in wound healing in the conducting airway is less well understood. We defined the pattern of expression of TFF1, TFF2 and TFF3 in the airways of mice during repair of both severe (300mg/kg) and moderate (200mg/kg) naphthalene induced Clara cell injury. Quantitative real-time PCR for TFF mRNA expression and immunohistochemistry for protein expression were applied to airway samples obtained by microdissection of airway trees or to fixed lung tissue from mice at 6 and 24 hours and 4 and 7 days after exposure to either naphthalene or an oil (vehicle) control. All three frefoil factors were expressed in normal whole lung and airways. TFF2 was the most abundant and was enriched in airways. Injury of the airway epithelium by 300 mg/kg naphthalene caused a significant induction of TFF1 gene expression at 24hrs, 4 and 7 days. In contrast TFF2 was decreased in the high dose group at 24 hrs and 4 days but returned to baseline levels by 7 days. TFF3 gene expression was not significantly changed at any timepoint. Protein localization via immunohistochemistry did not directly correlate with the gene expression measurements. TFF 1 and 3 expression was most intense in the degenerating Clara cells in the injury target zone at 6 and 24 hrs. Following the acute injury phase TFF1 and 3 were localized to the luminal apices of repairing epithelial cells and to the adjacent mesenchyme in focal regions that correlated with bifurcations and the bronchoalveolar duct junction. The temporal pattern of increases in TFF1, TFF2 and TFF3 indicate a role in cell death as well as proliferation, migration and differentiation phases of airway epithelial repair.

Key Words: Lung; Clara cell; naphthalene; TFF1; TFF3.

Current address of Melanie A. Greeley: WIL Research Laboratories, 1407 George Rd., Ashland, OH 44805, (419) 289-8700, mgreeley{at}wilresearch.com


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