Neuroendocrine differentiation, neuropeptides, and neprilysin.

Pulmonary neuroendocrine cells exhibit highly specialized differentiation with a neurosecretory phenotype and significant bioactive peptide hormone content. In addition to these functions, pulmonary neuroendocrine cells have been demonstrated to act as chemoreceptors for hypoxia (1). Specific pulmonary disorders, including bronchopulmonary dysplasia, bronchiectasis, cystic fibrosis, pulmonary hypertension, eosinophilic granuloma, respiratory bronchiolitis, emphysema, and chronic bronchitis have been associated with pulmonary neuroendocrine cell hyperplasia (reviewed in 2). A series of elegant studies (reviewed in 3) demonstrate a role for bombesin-like peptides in promoting fetal lung development and surfactant maturation. Recently, administration of antibombesin antibody in a baboon model of bronchopulmonary dysplasia has resulted in clinical and pathologic improvement (3). Thus, in the prenatal setting, neuroendocrine cell-derived bombesin-like peptides have a beneficial effect, whereas in the setting of bronchopulmonary dysplasia, excessive concentrations of the same peptides contribute to disease. Therefore, the control of pulmonary neuroendocrine cell numbers is clearly of clinical relevance. The processes of neuroendocrine cell differentiation, proliferation, and apoptosis combine to determine pulmonary neuroendocrine cell numbers. In this issue, Willett and colleagues (4) demonstrate that inhibition of neuropeptide degradation may increase neuroendocrine cell hyperplasia, perhaps by an autocrine effect. The stem cells that act as progenitors for airway neuroendocrine cells are not fully defined, nor are the cells into which the airway neuroendocrine cell may transdifferentiate. The recent report of dual CC10/CGRP positive cells in the mouse airway after injury suggests a close relationship between the Clara and neuroendocrine cell lineages (5). Some of the transcriptional events regulating pulmonary neuroendocrine cell differentiation are beginning to be defined. Members of the achaete-scute family of basic helix-loop-helix transcription factors play critical roles in the development of neuronal structures in Drosophila as well as vertebrates. Mice homozygous for null mutations in the mouse achaete-scute homologue-1 (MASH1) exhibit multiple abnormalities in olfactory and enteric neurons and die within 24 h of birth. Of interest, MASH1 2 / 2