Pulmonary neuroepithelial bodies are polymodal airway sensors: Evidence for CO₂/H⁺sensing

Abstract

sensors that release serotonin (5-HT) in response to hypoxia. Direct evidence that NEB cells also respond to airway hypercapnia/acidosis (CO 2/H ϩ ) is presently lacking. We tested the effects of CO2/H ϩ alone or in combination with hypoxia on 5-HT release from intact NEB cells in a neonatal hamster lung slice model. For the detection of 5-HT release we used carbon fiber amperometry. Fluorescence Ca 2ϩ imaging method was used to assess CO 2/H ϩ -evoked changes in intracellular Ca 2ϩ . Exposure to 10 and 20% CO2 or pH 6.8 -7.2 evoked significant release of 5-HT with a distinct rise in intracellular Ca 2ϩ in hamster NEBs. This secretory response was dependent on the voltagegated entry of extracellular Ca 2ϩ . Moreover, the combined effects of hypercapnia and hypoxia were additive. Critically, an inhibitor of carbonic anhydrase (CA), acetazolamide, suppressed CO 2/H ϩ -mediated 5-HT release. The expression of mRNAs for various CA isotypes, including CAII, was identified in NEB cells from human lung, and protein expression was confirmed by immunohistochemistry using a specific anti-CAII antibody on sections of human and hamster lung. Taken together our findings provide strong evidence for CO 2/H ϩ sensing by NEB cells and support their role as polymodal airway sensors with as yet to be defined functions under normal and disease conditions. chemosensing; serotonin AIRWAY EPITHELIUM OF HUMAN and animal lungs contains innervated clusters of amine (serotonin, 5-HT) and peptide-producing cells referred to as neuroepithelial bodies or NEBs (7,20,34). NEBs are numerous in fetal/neonatal lungs, and their density decreases with postnatal lung growth, suggesting important function during perinatal adaptation to air breathing (3). Although the precise function of NEB remains to be determined, a number of studies suggest that they function as airway O 2 sensors (5, 36). Recent cellular and molecular studies of native NEB cells and related tumor cell lines have identified a membrane-delimited O 2 -sensing molecular complex (O 2 sensor) composed of an O 2 -sensing protein (multicomponent NADPH oxidase) coupled to an O 2 -sensitive K ϩ channel (6,25,26,35 channels with influx of extracellular Ca 2ϩ triggering exocytosis and release of 5-HT and peptide mediators. These neurochemicals may act locally on surrounding lung tissues or as neurotransmitters via complex NEB innervation transmitting stimuli to the brain stem (16). NEBs exhibit many features similar to the carotid body (CB) glomus cells, the well-characterized polymodal arterial chemoreceptors monitoring changes in partial pressure of O 2 /CO 2 and pH in the blood (14). Because the CB, the principal arterial chemoreceptors, are immature at birth, it has been suggested that during the perinatal period NEBs could serve a function analogous to the CB.Although earlier studies by Lauweryns et al. (18) suggested that NEBs in neonatal rabbit lungs are sensitive to hypoxia and hypercapnia, these findings could not be replicated in subsequent studies (19). Other investigators have fo...

Nominal carbonic anhydrase activity minimizes airway-surface liquid pH changes during breathing

“…) and by mRNA detection in human neuroendocrine bodies (Livermore et al. ), but not on surface epithelia of the airways. Carbonic anhydrase XIV was the only membrane‐bound isozyme detected at the mRNA level in human infant lung epithelium (Livermore et al.…”

High serum serotonin in sudden infant death syndrome

“…Greater than 90% of the peripheral 5-HT is produced in the gut EC cells, and these cells are known to increase their secretion of 5-HT under various conditions, including hypoxia (35) and infection (36). PNEC and NEBs cells of the lung function as airway oxygen/carbon dioxide sensors and release 5-HT in a dosedependent manner in response to hypoxia (37,38). Although there have been no reports in SIDS of increased 5-HT production from EC cells of the gut, hyperplasia and hypertrophy of PNEC/ NEB within the lungs of infants dying of SIDS have been reported, and secretory products of these PNEC/NEB cells have been proposed previously as a potential biological marker of SIDS (38).…”

Signals of vagal circuits engaging with AKT1 in α7 nAChR+CD11b+ cells lessen E. coli and LPS-induced acute inflammatory injury

“…Some airway sensors are predominantly innervated by vagal afferent fibers derived from the nodose ganglion [27]. The information of lung infection and inflammation is transmitted via the afferent arm to the NTS.…”