Bcl-2 sustains increased mucous and epithelial cell numbers in metaplastic airway epithelium.
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.
Harris
J Foster
JF
Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE, Albuquerque, NM 87108, USA.
Fischer
Mark J
MJ
Hotchkiss
Jon R
JR
Monia
Brett P
BP
Randell
Scott H
SH
Harkema
Jack R
JR
Tesfaigzi
Yohannes
Y
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009297:Nasal Mucosa / Q000378:metabolism* / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D011336:Probability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D012680:Sensitivity and Specificity; D013045:Species Specificity; D015854:Up-Regulation
D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2