Number and proliferation of neuroendocrine cells in normal human airway epithelium.

Abstract

Pulmonary neuroendocrine cells (PNECs) are ubiquitous in human adult airway epithelium, and are implicated in pulmonary disease as PNEC hyperplasia has been described in a great number of different pulmonary lesions. The purpose of this study was to determine the baseline quantity and proliferative fraction of adult PNECs in the conducting airway epithelium of normal lungs. Autopsy was performed within 6 h of death on 250 subjects. In 9 of 250 cases without pulmonary disease, seven sequential samples were taken from trachea down to respiratory bronchioles, fixed in formalin, and embedded in paraffin. After microwave pretreatment in citrate buffer, sequential immunohistochemical staining was carried out, using MIB-1 (antibody directed against recombinant parts of the Ki-67 antigen) as marker for the proliferation fraction and chromogranin-A (CgA) for the identification of PNECs. Quantification of all epithelial cells of the conducting airways, MIB-1, and CgA immunoreactive cells, and length of basement membrane was interactively performed using image analysis. The results show that microwave treatment significantly enhances the sensitivity of CgA without loss of specificity. In total, 326,500 epithelial cells and 105 cm of basement membrane (BM) length were counted (3,101 cells/cm BM). The proliferation fraction of all epithelial cells was 0.76 +/- 0.53% (mean +/- SD). No mitosis was seen. The mean quantity of PNECs was 0.41 +/- 0.17% of all epithelial cells (12.5 cells/cm BM). Many dendritic PNEC processes parallel to the basement membrane could be appreciated between adjacent epithelial cells. No difference in the number of PNECs was found between large and small conducting airways. PNECs were not observed in the alveoli. Only 13 PNECs were immunoreactive for MIB-1; the proliferative fraction of PNECs was 1 to 2%. In histologically normal adult human conducting airway epithelium, the average overall proliferation fraction is 0.76%. The proliferation fraction of PNECs is equal to the overall proliferative fraction. The fraction of PNECs is 0.41%, using anti-CgA antiserum after microwave pretreatment of slides, 12 times more than previously reported. Many dendritic neuroendocrine cell processes were seen between non-neuroendocrine epithelial cells adjacent to the basement membrane. The widely held belief that neuroendocrine cells are of little importance in the adult lung is contradicted by the relative high density of PNECs and its cytoplasmic processers.

Up-regulation of Expression of the Ubiquitin Carboxyl-Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers

“…39), expression of many neuroendocrine cell-specific genes could not be detected in the brushed samples of large and small airway epithelium. Using the criteria of an Affymetrix Detection Call of Present in z50% samples, the neuroendocrine genes that were expressed (other than UCHL1 in smokers) included GRP, CHGA, neuron-specific enolase, and SCG2.…”

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo

“…Although PNECs constitute a very small cell population of the airways and are characterised by a low rate of proliferation [36], PNECs may proliferate considerably under certain conditions. Experimentally induced hyperplasia of PNECs has been observed to occur in response to various toxic gases or carcinogenic stimuli [37].…”

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

“…Pulmonary neuroendocrine cells are evenly distributed throughout the airways, but absent from the alveoli, and comprise 0.4% of all lung epithelial cells (Boers et al 1996). In response to various triggers, reactive neuroendocrine cell hyperplasia can occur, which is not associated with the development of pulmonary carcinoids.…”