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.