Pulmonary neuroepithelial bodies as airway sensors: putative role in the generation of dyspnea

Domnik, Nicolle J.; Cutz, Ernest

doi:10.1016/j.coph.2011.04.003

Cited by 38 publications

(20 citation statements)

References 51 publications

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“…However, immunostaining of human tissues with the neuronal marker, neurofilament H, revealed a possible innervation of human PNECs, as has been described for NEBs in some rodent species. These findings further suggest that human PNECs are not likely to be homologous to the previously described neonatal human PNECs and NEBs, or other types of adult PNECs that have been described in animal models (29,30,32,35,44). We currently do not understand why PNECs are different in primates relative to other mammals.…”

Section: Discussionmentioning

confidence: 51%

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Karp

Brody

et al. 2014

Am J Respir Cell Mol Biol

120

108

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The mammalian airways are sensitive to inhaled stimuli, and airway diseases are characterized by hypersensitivity to volatile stimuli, such as perfumes, industrial solvents, and others. However, the identity and function of the cells in the airway that can sense volatile chemicals remain uncertain, particularly in humans. Here, we show that solitary pulmonary neuroendocrine cells (PNECs), which are morphologically distinct and physiologically undefined, might serve as chemosensory cells in human airways. This conclusion is based on our finding that some human PNECs expressed members of the olfactory receptor (OR) family in vivo and in primary cell culture, and are anatomically positioned in the airway epithelium to respond to inhaled volatile chemicals. Furthermore, apical exposure of primaryculture human airway epithelial cells to volatile chemicals decreased levels of serotonin in PNECs, and the led to the release of the neuropeptide calcitonin gene-related peptide (CGRP) to the basal medium. These data suggest that volatile stimulation of PNECs can lead to the secretion of factors that are capable of stimulating the corresponding receptors in the lung epithelium. We also found that the distribution of serotonin and neuropeptide receptors may change in chronic obstructive pulmonary disease, suggesting that increased PNEC-dependent chemoresponsiveness might contribute to the altered sensitivity to volatile stimuli in this disease. Together, these data indicate that human airway epithelia harbor specialized cells that respond to volatile chemical stimuli, and may help to explain clinical observations of odorant-induced airway reactions.

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Section: Discussionmentioning

confidence: 51%

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Karp

Brody

et al. 2014

Am J Respir Cell Mol Biol

120

108

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“…As development continues, chromaffin cells lose their sensitivity to hypoxia as the carotid body, the primary peripheral O 2 -sensing organ, begins to mature (Donnelly, 2005). Pulmonary NEBs are also O 2 sensitive and are believed to be important during the perinatal period (Domnik and Cutz, 2011). In anamniotic vertebrates, such as amphibians, O 2 sensing occurs in the gills of water-breathing larvae (reviewed by Jonz and Nurse, 2006), as it does in fish, but after the gills degenerate during metamorphosis, a carotid body-like organ, called the carotid labyrinth, develops and takes over as the primary peripheral chemosensory organ in adults (Kusakabe, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Respiratory chemoreceptors are specialized cells that detect changes in the partial pressure of environmental or arterial O 2 and CO 2 (P O2 and P CO2 ) and initiate compensatory changes in ventilation and heart rate (Milsom and Burleson, 2007;López-Barneo et al, 2008;Perry et al, 2009). Respiratory chemoreceptors are well described in mammals (López-Barneo et al, 2008;Nurse et al, 2009;Domnik and Cutz, 2011). In teleost fish, O 2 -and CO 2 -sensitive neuroepithelial cells (NECs) of the gills are homologues of mammalian chemoreceptors.…”

Section: Introductionmentioning

confidence: 99%

Serotonergic neuroepithelial cells of the skin in developing zebrafish: morphology, innervation and oxygen-sensitive properties

Coccimiglio

Jonz

2012

Journal of Experimental Biology

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SUMMARYIn teleost fish, O 2 chemoreceptors of the gills (neuroepithelial cells or NECs) initiate cardiorespiratory reflexes during hypoxia. In developing zebrafish, hyperventilatory and behavioural responses to hypoxia are observed before development of gill NECs, indicating that extrabranchial chemoreceptors mediate these responses in embryos. We have characterised a population of cells of the skin in developing zebrafish that resemble O 2 -chemoreceptive gill NECs. Skin NECs were identified by serotonin immunolabelling and were distributed over the entire skin surface. These cells contained synaptic vesicles and were associated with nerve fibres. Skin NECs were first evident in embryos 24-26hpost-fertilisation (h.p.f.), and embryos developed a behavioural response to hypoxia between 24 and 48h.p.f. The total number of NECs declined with age from approximately 300cells per larva at 3days post-fertilisation (d.p.f.) to ~120cells at 7d.p.f., and were rarely observed in adults. Acclimation to hypoxia (30mmHg) or hyperoxia (300mmHg) resulted in delayed or accelerated development, respectively, of peak resting ventilatory frequency and produced changes in the ventilatory response to hypoxia. In hypoxia-acclimated larvae, the temporal pattern of skin NECs was altered such that the number of cells did not decrease with age. By contrast, hyperoxia produced a more rapid decline in NEC number. The neurotoxin 6-hydroxydopamine degraded catecholaminergic nerve terminals that made contact with skin NECs and eliminated the hyperventilatory response to hypoxia. These results indicate that skin NECs are sensitive to changes in O 2 and suggest that they may play a role in initiating responses to hypoxia in developing zebrafish.

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“…The diverse and often opposite effects of secreted amines and peptides from NEBs reveal the complex nature of PNEC function that remains to be elucidated. Decades of studies on PNECs culminate in the current view that PNECs function in airway oxygen sensing, regulate pulmonary blood flow, control bronchial tonus, modulate immune responses, and maintain a stem cell niche (5,6). No other cell type in the lung exhibits such a diverse array of activities.…”

mentioning

confidence: 99%

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Song

Yao

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

247

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Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC) and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the calcitonin gene-related peptide (CGRP) locus that encodes a major peptide in PNECs. The CGRP CreER mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which CGRP CreER was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.progenitor | naphthalene | cell of origin | tumor suppressor gene

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Pulmonary neuroepithelial bodies as airway sensors: putative role in the generation of dyspnea

Cited by 38 publications

References 51 publications

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Serotonergic neuroepithelial cells of the skin in developing zebrafish: morphology, innervation and oxygen-sensitive properties

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

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