Conditional Clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells

The neuroepithelial body (NEB) is a highly dynamic structure that responds to chronic airway injury through hyperplasia of associated pulmonary neuroe ndocrine (PNE) cells. Although NEB dysplasia is correlated with preneoplast ic conditions and PNE cells are thought to serve as a precursor for develop ment of small cell lung carcinoma, mechanisms regulating expansion of the P NE cell population are not well understood. Based on studies performed in a nimal models, it has been suggested that NEB-associated progenitor cells th at are phenotypically distinct from PNE cells contribute to PNE cell hyperp lasia. We have previously used a Clara cell-specific toxicant, naphthalene, to induce airway injury in mice and have demonstrated that naphthalene-res istant Clara cells, characterized by their expression of Clara cell secreto ry protein (CCSP), and PNE cells contribute to airway repair and associated hyperplasia of NEBs. This study was conducted to define the contribution o f NEB-associated CCSP-expressing progenitor cells to PNE cell hyperplasia a fter Clara cell ablation. Transgenic (CCtk) mice were generated in which he rpes simplex virus thymidine kinase was expressed within all CCSP-expressin g cells of the conducting airway epithelium through the use of transcriptio nal regulatory elements from the mouse CCSP promoter. Chronic administratio n of ganciclovir (GCV) to CCtk transgenic mice resulted in selective ablati on of CCSP-expressing cells within conducting airways. Proliferation and hy perplasia of PNE cells occurred in the absence of detectable proliferation among any other residual airway epithelial cell populations. These results demonstrate that PNE cells function as a self-renewing progenitor populatio n and that NEB-associated Clara cells are not necessary for PNE cell hyperp lasia.