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Activation of Calcitonin Gene-Related Peptide Receptor during Ozone Inhalation Contributes to Airway Epithelial Injury and Repair

¹ The Center for Comparative Respiratory Biology and Medicine, School of Veterinary Medicine, University of California, Davis, CA 95616 USA
² Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA 95616 USA

Correspondence: Edward S. Schelegle, PhD, Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, One Shields Ave., Davis, CA 95616, USA; phone: (530) 752-1177; fax (530) 752-7690; e-mail:esschelegle{at}ucdavis.edu.

The authors investigated the importance of the neuropeptide, calcitonin gene-related peptide (CGRP), in epithelial injury, repair, and neutrophil emigration after ozone exposure. Wistar rats were administered either a CGRP-receptor antagonist (CGRP_8–37) or saline and exposed to 8 hours of 1-ppm ozone or filtered air with an 8-hour postexposure period. Immediately after exposure, ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, airway dissected lung lobes were stained for 5'-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Positive epithelial cells were quantified in specific airway generations. Rats treated with CGRP_8–37 had significantly reduced epithelial injury in terminal bronchioles and reduced epithelial proliferation in proximal airways and terminal bronchioles. Bronchoalveolar lavage and sections of terminal bronchioles showed no significant difference in the number of neutrophils emigrating into airways in CGRP_8–37-treated rats. The airway epithelial cell line, HBE-1, showed no difference in the number of oxidant stress positive cells during exposure to hydrogen peroxide and a range of CGRP_8–37 doses, demonstrating no antioxidant effect of CGRP_8–37. We conclude that activation of CGRP receptors during ozone inhalation contributes to airway epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.

Key Words: oxidant airway injury • neuropeptide • neutrophil emigration • cell proliferation • calcitonin gene-related peptide receptor

Abbreviations: AEC, 3-amino-9-ethylcarbazole • BAL, bronchoalveolar lavage • BrdU, 5'-bromo-2'-deoxyuridine • CA, central airway • CGRP, calcitonin gene related peptide • CGRP_8–37, CGRP receptor antagonist 8–37 peptide fragment • FA, filtered air • HBE-1, human airway epithelial cell line • H₂O₂, hydrogen peroxide • IL-1β, interleukin 1 beta • LP PA, long path proximal airway • LP TB, long path terminal bronchiole • NK, neurokinin • NK-1, neurokinin 1 • PPM, parts per million • SP PA, short path proximal airway • SP TB, short path terminal bronchiole

This version was published on October 1, 2009

Toxicologic Pathology, Vol. 37, No. 6, 805-813 (2009)
DOI: 10.1177/0192623309345691


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