Vol. 86, Issue 3, 787-788, March 1999
INVITED EDITORIAL
Invited Editorial on "Evidence that neuroepithelial endocrine cells
control the spontaneous tone in guinea pig tracheal
preparations"
Ernest
Cutz and
Adele
Jackson
Department of Paediatric Laboratory Medicine, Research Institute,
Hospital for Sick Children, and University of Toronto, Toronto,
Ontario M5G 1X8, Canada
 |
ARTICLE |
A RELATIVELY RARE AND OBSCURE airway epithelial cell
type, the so-called neuroepithelial endocrine (NEE) cell, has until
recently been considered a morphological curiosity with undefined
function. These cells, discovered over 50 years ago, were identified as argyrophilic cells distributed within the airway epithelium of human
and animal lungs. Subsequent immunohistochemical investigations confirmed the presence of biogenic amine [serotonin (5-HT)]
and of several peptide hormones, including bombesin, calcitonin,
calcitonin gene-related peptide, CCK, Leu-enkephalin, as well as a
number of neural and neuroendocrine markers (see Refs. 1, 2, and 10 for
reviews). The identification of endocrine and neurallike features led
to the designation of the pulmonary neuroendocrine cell (PNEC) system
comprising solitary PNEC and innervated PNEC clusters, termed
"neuroepithelial bodies" (NEB) (2, 6, 7). Whereas solitary PNEC
and NEB exhibit identical phenotype in terms of amine, peptide, and
neuroendocrine marker expression, only NEB appear to be innervated and
occur exclusively within the intrapulmonary airways (7). In contrast,
solitary PNEC often form thin apical or lateral cytoplasmic processes
and are distributed within the epithelium lining the larynx, trachea,
and bronchi, down to the bronchiole-alveolar junction (1, 2, 10).
Based on these morphological findings, it is expected that NEB
signaling involves input and modulation via the central nervous system,
whereas solitary PNEC may act locally on adjacent cells and/or critical
anatomic structures (i.e., bronchial smooth muscle). During the past 20 years, a great deal of information on the morphology of PNEC system has
been generated, but their precise function in the lung remains largely
unknown, including the functional relationship between solitary PNEC
and NEB.
Current consensus suggests a multifunctional role for PNEC system in
mammalian lungs, with three main hypotheses advanced. First, a function
of airway chemoreceptors (relevant mostly to NEB) acting
as transducers of hypoxia stimulus via neural input, affecting the
control of breathing and/or other pulmonary function, has been
postulated (2, 6, 11). There is remarkable similarity between NEB cells
and well-defined chemoreceptors, the glomus cells of the carotid body.
As glomus cells, NEB cells release amine (5-HT) in response to hypoxia
(3, 6); and an O2-sensing mechanism has been demonstrated at the cellular and molecular level
(15, 16). Recent studies in our laboratory have shown that
NEB cells exhibit membrane properties of excitable cells, since they
possess voltage-activated K+,
Na+ and
Ca2+ currents (4, 15-17). We
have also shown that hypoxia (PO2 25-30 Torr) reversibly reduced
K+ current, whereas
Na+ and
Ca2+ currents were unaffected (4,
16, 17). In related studies, we have further shown that the gating of
O2-sensitive
K+ current may be modulated by
reactive oxygen intermediates such as
H2O2
(4, 15, 17). The evidence for this included the demonstration in NEB
cells of a
H2O2-generating
NADPH oxidase (16, 18); also, diphenylene iodonium (DPI), an inhibitor
of the oxidase, suppressed
O2-sensitive
K+ current, whereas direct
application of
H2O2
augmented the K+ current (4,
15-17). Thus a membrane model for
O2 sensing has been proposed on
the basis of an interaction between
O2-sensing protein (NADPH oxidase)
and O2-sensitive
K+ channel (15, 17). The second
hypothesis for the function of PNEC relates mostly to the developing
lung and is based on known growth factorlike properties of bombesin and
related peptides, highly expressed in PNEC of human fetal lung (see
Ref. 14 for review). The third hypothesis postulates effects via
adjacent vascular structures and/or modulation of bronchomotor tone by targeting airway smooth muscle and associated nerve endings in proximity to PNEC (6, 11). At present, there is no direct evidence in
support of the latter hypothesis.
A number of studies indicate that airway epithelium can modulate the
responsiveness of underlying smooth muscle in several ways; e.g., it
acts as a physical or metabolic barrier by restricting the access or by
inactivating potential constrictor (or relaxant) agonists to smooth
muscle or nerves, or the epithelium itself secretes factors (e.g.,
prostaglandins and other eicosanoids, 5-HT, calcitonin gene-related
peptide, cytokines, nitric oxide, epithelium-derived relaxing factor,
etc.) that modulate the activity of smooth muscle (12, 13). Removal of
epithelium from bronchi has been shown to increase the contractile
responses evoked by acetylcholine, histamine, and 5-HT, suggesting that
airway epithelial cells may generate an inhibitory signal to decrease
the responsiveness of bronchial smooth muscle to contractile agonists
and augment the effectiveness of inhibitory stimuli (8). Whether these effects are related to a specific airway epithelial cell has not been
previously investigated. The following paper by Skogvall et al. (9)
provides novel physiological evidence for involvement of
O2-sensing PNEC (term "NEE
cell" used by the authors) in the contractility of airway smooth
muscle in isolated tracheal preparations. Spontaneous tone in isolated
guinea pig tracheal preparations was assessed before and after
interference with NEE cell function, either via pharmacological agents
or by epithelium denudation.
After removal of the epithelium, the tracheal preparations failed to
develop a highly stable tone with repetitive bursts of oscillations
(i.e., complex spontaneous tone) in 12%
O2 (corresponding to arterial
O2 levels) and, instead, showed a
strong nonoscillating smooth tone normally observed in 94%
O2. In intact preparations, inhibition of
H2O2
production with DPI transformed the strong smooth tone to an
oscillating tone with less force in 94%
O2. In addition, exposure of
intact preparations to H2O2 transformed the tone from a complex type to one that is strong and smooth in 12%
O2. Hence, "silencing" or
"activating" O2-sensing
signal transduction in NEE cells with
H2O2
or DPI, respectively, altered the generation of spontaneous tracheal tone.
These findings suggest that solitary NEE cells in the tracheal
epithelium (as NEB in intrapulmonary airways) detect hypoxia via an
H2O2-producing
NADPH oxidase and a closely associated
H2O2-activated K+ channel (4, 15-17). Thus
it is postulated that powerful relaxing and contracting factors
released from NEE cells in response to different
O2 concentrations modulate the
responsiveness of the adjacent airway smooth muscle cells, which, in
turn, control the spontaneous tone of the trachea. Interestingly,
earlier studies have also shown that lowering the
PO2 induces epithelium-dependent relaxation of canine bronchi (5).
The significance and implications of the study by Skogvall et al. (9)
impact on several aspects of postulated PNEC function(s) in normal and
diseased lungs. The expression of an
O2-sensing mechanism shared by
both solitary PNEC and NEB could form a basis for a unifying hypothesis
subject to further studies. A natural stimulus (e.g.,
O2 concentration) transduced via
an O2 sensor on PNEC could
modulate various pulmonary homeostatic processes, including the airway
tone, pulmonary circulation, control of breathing, as well as lung
growth and differentiation. Furthermore, the loss or dysfunction of the
airway epithelium is a common feature of respiratory diseases
characterized by increased airway responsiveness, e.g., asthma and
bronchopulmonary dysplasia. It is of interest to note that hyperplasia
of PNEC has been reported in both conditions (2). It can also be
postulated that airway inflammation via local production of
O2-reactive intermediates,
cytokines, and related substances could interfere with the
O2 sensor and thus affect airway
responsiveness. Therefore, PNEC could be potential targets for novel
therapies. Finally, this neglected cell type has come of age and can
now resume its rightful place among other lung cells important in
pulmonary function in health and disease.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: E. Cutz,
Dept. of Pathology, Hospital for Sick Children, 555 University Ave.,
Toronto, Ontario, Canada M5G 1X8 (E-mail:
ernest.cutz{at}sickkids.on.ca).
| |
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