This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sunday, M. E. Articles by Willett, C. G. Search for Related Content PubMed PubMed Citation Articles by Sunday, M. E. Articles by Willett, C. G.

Induction and Spontaneous Regression of Intense Pulmonary Neuroendocrine Cell Differentiation in a Model of Preneoplastic Lung Injury¹

Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 [M. E. S.], and Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [C. G. W.]

Pulmonary neuroendocrine cell (PNEC) hyperplasia is associated with chronic lung diseases in humans, where it is thought to play a role in reparative responses to lung injury. To investigate the kinetics of strongly induced PNEC hyperplasia in an animal model, we exposed hamsters to a combination of hyperoxia (60% O₂) and diethylnitrosamine (DEN) for up to 20 weeks. We thus demonstrate not only the induction but also spontaneous regression of intense PNEC differentiation and growth, which are much more intense than those observed with DEN alone. Lung tissues were immunostained for serotonin, calcitonin gene-related peptide (CGRP), calcitonin (CT), and gastrin-releasing peptide (GRP) (mammalian bombesin). Between 9 and 12 weeks of treatment, the number of CGRP- and serotonin-positive neuroepithelial bodies per cm airway epithelium increased over 10-fold, and CT became detectable. The number of neuroepithelial bodies immunostained for CGRP, serotonin, and CT peaked at 12–14 weeks of treatment, thereafter regressing to near-control levels by 20 weeks, in spite of continued DEN/O₂ treatment. Simultaneously, by 6–7 weeks of treatment, there was a significant increase in the mean number of CGRP-positive cells per neuroepithelial body, which continued to rise up to double control levels, with a plateau at 13–20 weeks. GRP and pro-GRP immunostaining were not detectable at any time point. Polymerase chain reaction analyses of neuroendocrine-specific mRNAs demonstrated that CGRP, CT, and GRP mRNAs (normalized for ß-actin) peaked in lung tissues from most animals at 9–14 weeks after the beginning of DEN/O₂ treatment, with decreased expression at 16–20 weeks. These data suggest that regulation of levels of these neuropeptides may be primarily transcriptional. This model may be a valuable system for analyzing mechanisms of induction and regression of normal PNEC differentiation and growth.