NEC involvement in the pathogenesis of childhood disorders
As previously mentioned, abnormalities in the number, distribution and function of pulmonary NEC have been documented in a number of different pediatric lung disorders that include PH 3,18. In normal lungs the relative density of nerve fibers increases during childhood in the arteries of the respiratory unit. In pediatric PH, a premature innervation of these arteries by nerve fibers occurs and associated with release of vasoconstrictor peptides during the first year of life15,27. Pulmonary NEC may be involved in the pathophysiology of PH through the production and release of 5-hydroxytryptamine 5-HT, a potent vasoconstrictor, whose release is amplified by hypoxia 3,16. PNEC are situated in small peripheral airways and at bronchoalveolar portals, in close proximity to pulmonary arterioles that are involved in hypoxia induced vascular resistance 3. To date there are no studies of pulmonary NEC in pediatric PH, however, immunohistochemical studies of lungs from adult patients with PH, both primary and secondary to congenital heart disease, revealed significant hyperplasia of these cells in early stages of the disease 28. Significant hyperplasia of pulmonary NEC has been described in infants with SIDS and CCHS, disorders characterized by dysfunction of respiratory control, and in the “pre-surfactant era” BPD, possibly related to chronic hypoxia and/or release of mitogenic inflammatory cytokines release of inflammatory cytokines that could stimulate the mitogenesis of PNEC/NEB directly or enhance recruitment from precursor cells3,15,29,30. The increased release of bombesin-like peptides (BLP) by pulmonary NEC in BPD has been attributed to the lung inflammatory response observed in this disorder but also questioned as a response to lung injury3,31,32. Increased levels of BLP are detectable in urine of infants with BPD that exhibit a variety of physiological abnormalities, including pulmonary hypertension, airway hyperreactivity, and increased apneic spells 33. Finally, in CF reduction in neuropeptides secretion by CFTR-deficient NEC could exacerbate the disease process by negatively affecting composition of periciliary fluid, and eventually leading to airway plugging and obstruction 3,34. A recent study on lung tissues from CFTR_/_ deficient mice, showed altered distribution and frequency of pulmonary NEC/NEB, abnormal innervation with reduced airway size during different developmental stages, suggesting an intrinsic abnormality 17. Through potentiating cholinergic neurotransmission, neuropeptides can act on bronchial smooth muscle, mucosal vasculature and submucosal glands and induce airflow obstruction and by promoting recruitment and activation of granulocytes, exacerbate neurogenic inflammation35,36. Pulmonary NEC may play a proinflammatory role via production of neuropeptides in these pathologies and possibly, as will be reviewed in the next two paragraphs, in respiratory virus-induced airway diseases. These latter disorders are characterized by inflammation, release of oxygen radicals, injury to airway structures, and, clinically by acute hypoxia, all stimuli that can activate pulmonary NEC causing release of bioactive neuropeptides16-18,25,30.