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Published ahead of print on December 23, 2004, doi:10.1164/rccm.200408-1108OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 764-772, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200408-1108OC

Original Article

Bcl-2 Sustains Increased Mucous and Epithelial Cell Numbers in Metaplastic Airway Epithelium

J. Foster Harris, Mark J. Fischer, Jon R. Hotchkiss, Brett P. Monia, Scott H. Randell, Jack R. Harkema and Yohannes Tesfaigzi

Lovelace Respiratory Research Institute, Albuquerque, New Mexico; Dow Chemical Company, Midland; Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan; Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina; ISIS Pharmaceuticals, Department of Molecular Pharmacology, Carlsbad, California

Correspondence and requests for reprints should be addressed to Yohannes Tesfaigzi, Ph.D., Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE, Albuquerque, NM 87108. E-mail: ytesfaig{at}lrri.org

Bcl-2, an inhibitor of apoptosis, is expressed in LPS-induced metaplastic goblet cells of rat airways. The present study investigated expression of Bcl-2 in airway mucous cells of persons with cystic fibrosis and tested in rats and mice whether its expression is responsible for sustaining metaplastic mucous cells. A significantly higher percentage of mucous cells expressed Bcl-2 in humans with cystic fibrosis compared with control subjects with no disease or subjects with other diseases. In LPS-instilled F344/N rats, the percentage of Bcl-2–positive mucous cells was decreased to background levels before the resolution of goblet cell metaplasia. Furthermore, intraperitoneal injection of rats with antisense oligonucleotides significantly reduced Bcl-2 expression and goblet cell metaplasia in nasal and pulmonary airway epithelia in rats. In contrast, sustained expression of Bcl-2 in transgenic mice by a metallothionein promoter caused increased LPS-induced goblet cell metaplasia over 8 days compared with wild-type mice. These studies demonstrate that Bcl-2 expression sustains goblet cell metaplasia in various species, that epithelial cell numbers are directly linked to the regulation of the numbers of goblet cells, and that downregulating Bcl-2 expression reduces goblet cell metaplasia.

Key Words: apoptosis • antisense oligonucleotides • cystic fibrosis • inflammation • LPS




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