The pulmonary NEC system
The pulmonary NEC system consists of solitary cells and distinctive clusters of these cells, termed neuroepithelial bodies (NEB), localized in the airway epithelium 3. Pulmonary NEC express a variety of bioactive substances, including amines (serotonin and 5-HT) and neuropeptides (calcitonin gene-related peptide, gamma-aminobutyric acid, vasoactive intestinal polypeptide and bombesin). Pulmonary NEC/NEB are found in all fetal stages, at which time they are intimately involved in the regulation of lung development 3,9,15. In fetal life, physiological hypoxia and mechanical stretch caused by fluid dynamics in the airway lumen upregulate pulmonary NEC functions, promoting epithelial cell proliferation, branching morphogenesis and type-II pneumocytes differentiation15. Mechanical-stretch-induced 5-HT release from NEC is mediated by mechanosensitive channels, independent of the exocytic pathway. In contrast, hypoxia-induced secretion of 5-HT and of neuropeptides occurs principally via classical exocytosis of dense core vesicles, a process mediated by voltage activated Ca++ channels without apparent involvement of mechanosensitive channels 3. After birth, pulmonary NEC decrease and often disappear with lung maturation by 1-2 years of age 15. This may not be the case in conditions of pathology, such as pediatric PH, BPD, SIDS, CCHS and CF 3,15-18. Acute or persistent hypoxia and injury to the airways, features of some of these disorders, are recognized stimuli that can activate pulmonary NEC inducing release of bioactive neuropeptides, such as bombesin, which can modulate lung damage, as shown in premature infants with BPD, or trigger smooth muscle contraction, as shown in NEHI 3,9,15-18. In this latter disorder, a predominant abundance of pulmonary bombesin-positive NEC in small airways and distal bronchiole has been described as the characteristic finding 18-20. A bombesin-induced airflow limitation at that level is consistent with the clinical presentation, i.e. small airway obstruction and air-trapping7,18.