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.

Proliferative lesions in the rodent nasal cavity are reviewed; attempt was made to compare species affected, sex differences, strain differences, route of administration and tumor types occurring both spontaneously and after induction by different chemicals. This review is not meant to be all inclusive but to be representative of observed trends. Our general conclusions in this paper are that: 1) spontaneous nasal tumors in rodents are very rare; 2) spontaneous nasal tumors in rats are most often squamous cell tumors, whereas hemangiomas or respiratory adenomas predominate in mice and squamous cell tumors are rare; 3) rats are usually more susceptible to the induction of epithelial tumors of the nasal cavity than mice; 4) chemically-induced hemangiomas and hemangiosarcomas of the nasal cavity have only been reported in mice; 5) tumors of the olfactory epithelium are almost uniformly malignant and invasive, while nonsquamous tumors of the respiratory epithelium are typically less invasive; 6) chemically-induced tumors of the olfactory region, either mesenchymal or epithelial, do not always require an inhalation route of exposure but may occur by systemic targeting of this region; and 7) chemicals inducing tumors in the olfactory region often produce a variety of tumor morphologies in this location as well as squamous and polypoid tumors of the transitional region. More work will be needed to illucidate the mechanisms of nasal carcinogenesis and to further refine the current tumor classification system.

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