Published ahead of print on December 23, 2004, doi:10.1164/rccm.200408-1108OC Am. J. Respir. Crit. Care Med., Volume 171, Number 7, April 2005, 764-772 A more recent version of this article appeared on April 1, 2005
Submitted on August 24, 2004 Bcl-2 Sustains Increased Mucous and Epithelial Cell Numbers in Metaplastic Airway EpitheliumJ. Foster Harris1,1 Department of Pathophysiology, Lovelace Respiratory Research Institute, Albuquerque, NM, USA, 2 The Dow Chemical Company, Midland, MI, USA, 3 Department of Molecular Pharmocology, ISIS Pharmaceuticals, Carlsbad, CA, USA, 4 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC, USA, 5 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA * To whom correspondence should be addressed. 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 studies 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 to non-diseased controls or subjects with other diseases. In LPS-instilled F344/N rats, the percentage of Bcl-2-positive mucous cells was decreased to background levels prior to 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 d compared to 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: LPS, apotosis, antisense oligonucleotide, cystic fibrosis, inflammation
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