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

Conditional Clara cell ablation reveals a self-renewing progenitor function of pulmonary... Abstract The neuroepithelial body (NEB) is a highly dynamic structure that responds to chronic airway injury through hyperplasia of associated pulmonary neuroendocrine (PNE) cells. Although NEB dysplasia is correlated with preneoplastic conditions and PNE cells are thought to serve as a precursor for development of small cell lung carcinoma, mechanisms regulating expansion of the PNE cell population are not well understood. Based on studies performed in animal models, it has been suggested that NEB-associated progenitor cells that are phenotypically distinct from PNE cells contribute to PNE cell hyperplasia. We have previously used a Clara cell-specific toxicant, naphthalene, to induce airway injury in mice and have demonstrated that naphthalene-resistant Clara cells, characterized by their expression of Clara cell secretory protein (CCSP), and PNE cells contribute to airway repair and associated hyperplasia of NEBs. This study was conducted to define the contribution of NEB-associated CCSP-expressing progenitor cells to PNE cell hyperplasia after Clara cell ablation. Transgenic ( CCtk ) mice were generated in which herpes simplex virus thymidine kinase was expressed within all CCSP-expressing cells of the conducting airway epithelium through the use of transcriptional regulatory elements from the mouse CCSP promoter. Chronic administration of ganciclovir (GCV) to CCtk transgenic mice resulted in selective ablation of CCSP-expressing cells within conducting airways. Proliferation and hyperplasia 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 population and that NEB-associated Clara cells are not necessary for PNE cell hyperplasia. lung airway stem cell herpes simplex virus thymidine kinase transgenic mice Footnotes Address for reprint requests and other correspondence: B. R. Stripp, Dept. of Environmental Medicine, Univ. of Rochester, Box EHSC, 575 Elmwood Ave., Rochester, NY 14642 (E-mail: barry_stripp@urmc.rochester.edu ). This study made use of core facilities within the University of Rochester Environmental Health Sciences Center (EHSC; supported by National Institute of Environmental Health Sciences Grant ES-01247) and was supported by a pilot project grant from the EHSC; National Heart, Lung, and Blood Institute Grant HL-64888; and the Patterson Trust. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 2000 the American Physiological Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Lung Cellular and Molecular Physiology The American Physiological Society

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

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
1040-0605
eISSN
1522-1504
Publisher site
See Article on Publisher Site

Abstract

Abstract The neuroepithelial body (NEB) is a highly dynamic structure that responds to chronic airway injury through hyperplasia of associated pulmonary neuroendocrine (PNE) cells. Although NEB dysplasia is correlated with preneoplastic conditions and PNE cells are thought to serve as a precursor for development of small cell lung carcinoma, mechanisms regulating expansion of the PNE cell population are not well understood. Based on studies performed in animal models, it has been suggested that NEB-associated progenitor cells that are phenotypically distinct from PNE cells contribute to PNE cell hyperplasia. We have previously used a Clara cell-specific toxicant, naphthalene, to induce airway injury in mice and have demonstrated that naphthalene-resistant Clara cells, characterized by their expression of Clara cell secretory protein (CCSP), and PNE cells contribute to airway repair and associated hyperplasia of NEBs. This study was conducted to define the contribution of NEB-associated CCSP-expressing progenitor cells to PNE cell hyperplasia after Clara cell ablation. Transgenic ( CCtk ) mice were generated in which herpes simplex virus thymidine kinase was expressed within all CCSP-expressing cells of the conducting airway epithelium through the use of transcriptional regulatory elements from the mouse CCSP promoter. Chronic administration of ganciclovir (GCV) to CCtk transgenic mice resulted in selective ablation of CCSP-expressing cells within conducting airways. Proliferation and hyperplasia 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 population and that NEB-associated Clara cells are not necessary for PNE cell hyperplasia. lung airway stem cell herpes simplex virus thymidine kinase transgenic mice Footnotes Address for reprint requests and other correspondence: B. R. Stripp, Dept. of Environmental Medicine, Univ. of Rochester, Box EHSC, 575 Elmwood Ave., Rochester, NY 14642 (E-mail: barry_stripp@urmc.rochester.edu ). This study made use of core facilities within the University of Rochester Environmental Health Sciences Center (EHSC; supported by National Institute of Environmental Health Sciences Grant ES-01247) and was supported by a pilot project grant from the EHSC; National Heart, Lung, and Blood Institute Grant HL-64888; and the Patterson Trust. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 2000 the American Physiological Society

Journal

AJP - Lung Cellular and Molecular PhysiologyThe American Physiological Society

Published: Jun 1, 2000

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