NEUROPHYSIOLOGY / Neuroendocrine Cells 149

Sudden infant death syndrome is another syndrome whose etiology is thought to be related to pathology of the central respiratory neural network causing a cessation of breathing. In this case, the exact site of the neuropathology is not known, although there is evidence that there are abnormalities in the regions of the ventral medulla that could affect the normal pattern of respiratory rhythm generation.
Irregular Breathing Patterns

There are a number of abnormal breathing patterns associated with disease processes. Because they can occur at any level of the brain, cerebral strokes can result in patterns that replicate those of early studies used to identify and characterize the neural components of the respiratory neural network. If the stroke occurs in the cortex, a waxing and waning of breathing occurs (CheyneStokes breathing) due to the loss of higher cortical inuences. A lesion in the diencephalon produces a rapid shallow breathing (central neurogenic hyperventilation), suggesting that the inhibitory inuences on the rate of breathing are removed. A stroke that lesions the rostral third of the pons could produce an apneustic pattern of breathing if there is an impaired function of the PRG. Strokes that produce lesions in the medullary centers could result in patterns of clustered breathing or ataxic breathing depending on how much of the neural circuitry they destroy. Other abnormal breathing patterns are associated with conditions such as congenital hypoventilation syndrome, obstructive sleep apnea syndrome (OSA), and Rett syndrome. The causes of these syndromes are not fully understood but are likely related to genetic factors or, in the case of OSA, a combination of genetic and acquired factors that compromise the upper airway.
See also: Breathing: Breathing in the Newborn; Fetal Breathing. Chemoreceptors: Central; Arterial. Diving. Exercise Physiology. High Altitude, Physiology and Diseases. Neuromuscular Disease: Lower Motor Neuron Diseases; Upper Motor Neuron Diseases. Neurophysiology: Neural Control of Airway Smooth Muscle. Obesity. Respiratory Muscles, Chest Wall, Diaphragm, and Other. Sleep Apnea: Overview; Adult; Children; Continuous Positive Airway Pressure Therapy; Drug Treatments; Genetics of Sleep Apnea. Sleep Disorders: Overview; Central Apnea (Ondines Curse); Hypoventilation; Upper Airway Resistance Syndrome. Space, Respiratory System. Sudden Infant Death Syndrome. Upper Airway Obstruction. Ventilation: Control.

Berger AJ and Bellingham MC (1995) Mechanisms of respiratory motor output. In: Dempsey JA and Pack AI (eds.) Lung Biology in Health and Disease, pp. 71149. New York: Dekker. Bianchi AL, Denavit-Saubie M, and Champagnat J (1995) Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiological Reviews 75: 145. Bonham AC (1995) Neruotransmitters in CNS control of breathing. Respiration Physiology 101: 219230. Del Negro CA, Wilson CG, Butera RJ, et al. (2001) Unstable breathing rhythms and quasiperiodicity in the pre-Botzinger complex. Advances in Experimental Medicine and Biology 499: 133138. Feldman JL, Mitchell GS, and Nattie EE (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annual Review of Neuroscience 26: 239266. Feldman JL and Smith JC (1995) Neural control of respiratory pattern in mammals: an overview. In: Dempsey JA and Pack AI (eds.) Lung Biology in Health and Disease, pp. 3969. New York: Dekker. Funk GD and Ramirez JM (2002) Neural control of breathing. Respiratory Physiology & Neurobiology 131: 13. Kinney HC and Filiano JJ (1988) Brainstem research in sudden infant death syndrome. Pediatrician 15: 240250. Ramirez JM, Zuperku EJ, Alheid GF, et al. (2002) Respiratory rhythm generation: converging concepts from in vitro and in vivo approaches? Respiratory Physiology & Neurobiology 131: 4356. Rekling JC and Feldman JL (1998) Pre-Botzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annual Review of Physiology 60: 385405. Richter DW, Manzke T, Wilken B, and Ponimaskin E (2003) Serotonin receptors: guardians of stable breathing. Trends in Molecular Medicine 9: 542548. Richter DW and Spyer KM (2001) Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends in Neuroscience 24: 464472.

Neuroendocrine Cells
E Cutz and H Yeger, The Hospital for Sick Children, Toronto, ON, Canada
& 2006 Elsevier Ltd. All rights reserved.

Abstract
Pulmonary neuroendocrine (NE) cells are widely distributed within the airway epithelium of mammalian lungs. NE cells are either found as a solitary cell or as part of distinctive innervated cell clusters, neuroepithelial bodies (NEBs), both of which have abundant cytoplasmic dense core vesicles (DCVs), the storage site for amine (serotonin, 5-HT) and peptides (bombesin, gastrin-releasing peptide) that act as neurotransmitters, neuromodulators, and growth factors. During lung development NE cells/ NEBs express a mixed epithelial, neural, and neuroendocrine phenotype and their differentiation is directed by proneural basic helixloophelix factors. In fetal lung, these cells appear numerous compared to the adult and are thought to be involved in lung morphogenesis, while postnatally NEBs function as hypoxia-sensitive airway chemoreceptors. Hypoxia activates a membrane-bound molecular complex composed of an oxygensensitive K channel coupled to a multicomponent NADPH

Further Reading
Berger AJ (2001) Central mechanisms of respiratory control. In: Hlastala MP and Berger AJ (eds.) Physiology of Respiration, pp. 134147. New York: Oxford University Press.

150 NEUROPHYSIOLOGY / Neuroendocrine Cells

oxidase leading to exocytosis of DCVs with release of 5-HT and other mediators acting locally or via vagal afferents transmitting the hypoxia signal to the brainstem. NEB cells also express multiple neurotransmitter receptors involved in the chemotransmission of hypoxia and other stimuli. The biological complexity and multifunctional nature of neuroendocrine cell systems implies wide-ranging involvement in normal lung functions and in the pathophysiology of a variety of pediatric as well as adult respiratory diseases including lung carcinogenesis.

Introduction
Pulmonary neuroendocrine (NE) cells were rst described 75 years ago when solitary and clusters of argyrophilic cells, analogous to similar cells in the gastrointestinal tract, were observed within the airway epithelium of human and animal lungs (Figure 1). These cells were thought to belong to a system of diffuse endocrine cells found in both endocrine and nonendocrine tissues. The term NE cell was adopted after the discovery of amine and peptide hormone expression by these cells and the recognition of their neural and endocrine phenotype.
Structure

At the light microscopy level, NE cells can now be identied by immunohistochemical methods using antibodies against a variety of neuroendocrine markers (Table 1). Solitary NE cells appear as askshaped cells with their apical surface reaching the airway lumen, or as elongated cells with lateral cytoplasmic processes extending along the basement membrane. The solitary NE cells are distributed throughout the epithelium of trachea and bronchi up

to the terminal bronchioles. Neuroepithelial bodies (NEBs) are corpuscular structures composed of 515 cells that are localized within the intrapulmonary airways and appear concentrated at airway bifurcations. Pulmonary NE cells/NEBs are relatively numerous in fetal/neonatal lungs compared to the adult. Solitary NE cells and NEBs constitute the neuroendocrine cell system with similar features and are therefore discussed collectively. Ultrastructurally, NE cells/NEBs are characterized by the presence of cytoplasmic dense core vesicles (DCVs), the storage site for amine and peptides (Figure 2(a)). The apical cell membrane forms short microvilli exposed to the airway lumen. The other cell organelles include small mitochondria, rough endoplasmic reticulum, ribosomes, microtubules, and bundles of microlaments. A well-developed Golgi complex shows a variety of associated vesicles related to the formation of DCVs. In NEBs of rabbit fetal and neonatal lungs two morphological types of nerve endings in contact with the granulated cells are found: afferent-like sensory nerve endings containing numerous small mitochondria (Figure 2(b)); and efferent-like nerve bers with agranular vesicles, microtubules, and sparse mitochondria (Figure 2(c)). Serial section studies have shown that these two types of nerve endings may be in continuity, an arrangement consistent with local modulation via an axon reex.
Innervation

The nature and origin of intraepithelial nerve endings in contact with NEB cells have been characterized in

Figure 1 Corpuscular NEB (arrow) and solitary pulmonary NE cells (arrowhead) within airway mucosa of newborn infant lung. Grimelius silvernitrate method; Magnication 600. Reproduced from Cutz E et al. (1995) Pulmonary neuroendocrine system: an overview of cell biology and pathology with emphasis on pediatric lung disease. Perspectives in Pediatric Pathology 18: 3270, with permission from S. Karger AG, Basel.

NEUROPHYSIOLOGY / Neuroendocrine Cells 151

Table 1 Immunohistochemical and molecular markers of NEB cells in mammalian lungsa Amine Serotonin (5hydroxytryptamine, 5-HT) Amine metabolizing enzymes Tryptophane hydroxylase Aromatic amino acid decarboxylase Regulatory peptides Bombesin/gastrin-releasing peptide (GRP) Calcitonin Calcitonin gene-related peptide (CGRP) Cholecystokinin (CCK) Substance P Somatostatin Endothelin Peptide YY Helodermin Pituitary adenyl cyclaseactivating protein Transcription factors Mash-1 Neuroendocrine/ neurosecretory markers Neuron specic enolase (NSE) Protein gene product 9.5 (PGP9.5) Chromogranin A NCAM/MOC-1 Leu 7/NHK Goa Synaptophysin Synaptic vesicle protein 2 (SV2) Synaptobrevin Synaptogamin SNAP-25 Calbindin D28K

Functional proteins NADPH oxidase (gp91phox, p22phox, p47phox, rac2)

demonstrated for gastrointestinal (GI) endocrine cells and islets of Langerhans). In early fetal lungs NE cells/ NEBs are the rst cell types to differentiate within primitive airway epithelium, implying that NE cells could promote differentiation of other pulmonary cell types. Several proneural and neurogenic genes belonging to the family of basic helixloophelix (bHLH) transcription factors have been identied that are involved in the ontogeny of NE cells/NEBs. The activator of mammalian homolog of achaete-scute complex (Mash-1) in mice and its human counterpart (Hash-1) are essential for pulmonary NE cell development. The disruption of the Mash-1 (Mash-1 / ) gene in mice resulted in failure of NE cell differentiation in the lung while GI endocrine cells were still present. Interestingly, lung morphogenesis did not appear to be affected by the loss of Mash-1 expression although these mice die shortly after birth due to respiratory failure. Ito and colleagues showed that the differentiation of NE cells was increased in hairy-enhancer-split (Hes-1)decient mice indicating that Hes-1 acts as a neurogenic gene repressor and that Mash-1 and Hes-1 likely act in concert with Notch/Notch ligand signaling pathways.

a There is marked species variation in the expression of different markers. However, the majority have been identied in NEB cells of human lung and/or experimental animals (i.e., rabbit, rat, hamster, mouse). Reproduced with permission from Cutz E, Fu XW, Yeger H, et al. (2003) Oxygen sensing in pulmonary neuroepithelial bodies and related tumor cell models. In: Lahiri S, Semenza GL, and Prabhakar NR (eds.) Oxygen Sensing Responses and Adaptation to Hypoxia, Lung Biology in Health and Disease, vol. 175, pp. 567 602. New York: Dekker. Copyright CRC Press, Boca Raton, FL.

Neuroendocrine Cell Functions in the Normal Lung

VanLommel and Lauweryns have proposed a dual role for NE cells/NEBs as having a local paracrine or endocrine role during intrauterine lung development and postnatally as airway chemoreceptors. The local paracrine functions are dependent on the synthesis and release of a number of biologically active substances including amine (serotonin, 5-hydroxytryptamine, 5-HT), peptides (e.g., bombesin/ gastrin-releasing peptide (GRP), CGRP, calcitonin, cholecystokinin, etc.) and other neuroendocrine molecules produced by NE cells/NEBs (Table 1). The predominant amine is 5-HT and is found in NE cells/ NEBs throughout the animal kingdom. The classical pharmacological activities of 5-HT in the lung include vasoconstriction, enhanced vascular permeability, and in some species bronchoconstriction. Other biological actions of 5-HT relevant to developing lung are that of a mitogen. The most prominent regulatory peptide identied in NE cells/NEBs of human lung is bombesin, a tetradecapeptide originally isolated from frog skin. This amphibian peptide is structurally related to a 27 amino acid mammalian peptide, GRP. Bombesin and GRP share an identical C-terminal decapeptide, accounting for the cross-reactivity of respective antibodies and for the similarities in their bioactivity.

the rabbit and rat lung. Although there are species differences, the predominant neural connections innervating NEB are sensory vagal afferents with nerve cell bodies residing in the nodose ganglion. In the rat, two additional components have been demonstrated: calcitonin gene-related peptide (CGRP) immunoreactive nerves derived from the spinal ganglia, and nitrergic nerve endings originating from peribronchial ganglia (Figure 3). The expression of several ionotropic neurotransmitter receptors together with complex innervation probably reect the multifunctional role of NEB in the lung.
Ontogeny and Differentiation

It is thought that pulmonary NE cells/NEB are derived from the foregut endoderm (as has been

152 NEUROPHYSIOLOGY / Neuroendocrine Cells

2 m

Figure 2 (a) Low magnication electron micrograph of bronchiolar NEB in rabbit neonatal lung located at a bifurcation. Apical surface of NEB cells form short microvilli (mv) exposed to airway lumen (AL). Columnar NEB cells with indented nuclei (Nu) contain numerous cytoplasmic dense core vesicles (DCV, arrows), and nerve endings in intercellular spaces (asterisk). The basal aspect of NEB rests on a basement membrane (arrowheads). (b) Afferent-like nerve ending containing numerous small mitochondria (mi). (c) Efferent-like nerve ending with small empty vesicles (ve). Typical DCV visible in adjacent cell cytoplasm (arrows).

Bombesin/GRP immunoreactivity has been demonstrated in NE cells/NEBs of human fetal, neonatal, and postnatal lungs throughout all ages. Expression of bombesin/GRP is developmentally regulated as high levels are detected during intrauterine life and in neonates, with significant decline postnatally. A single gene coding for human GRP has been identied on chromosome 18. Three distinct mRNA species encoding pro-GRP are generated from the primary transcript by alternative splicing. The highly conserved C-terminal region of bombesin and GRP is responsible for high-afnity binding to cell surface receptors mediating the various biological activities of bombesin-like peptides. At least three distinct

bombesin/GRP receptor subtypes have been identied. These receptors belong to a family of seven transmembrane G-protein-coupled cell surface receptors interacting with several intracellular signal transduction pathways. Sunday and colleagues investigated the potential role of bombesin/GRP in developing lung. They showed that the GRP gene was expressed in a proximal-to-distal pattern in human fetal lung in parallel with the growth of the developing airways. Exogenous bombesin was shown to act as a potent growth and differentiation factor for fetal murine lung in utero and for human and other species in lung organ culture. Bombesin-like peptides in vitro and

NEUROPHYSIOLOGY / Neuroendocrine Cells 153

Dorsal motor nucleus? Nucleus ambiguus? NTS Hyperactivity? Hyper-reactivity? Jugular ganglion

Cholinergic nonnitrergic

DRG (T1T6)

? Nodose ganglion Purinergic receptors Vagus nerve Myelinated (MBP+) Adenosine receptors? CGRP+ / SP+ capsaicin sensitive (P2X2?) / P2X3 receptor + CGRP-/capsaicin A(1?) adenosine insensitive NEB receptor + glutamatergic / CB+ CGRP+/SP+ Airway capsaicin sensitive epithelium

CB+ 5HT+ ACh+ CALC+ CGRP+

ATP+ ? Cholinergic Nitrergic noncholinergic nonnitrergic

? ? ? BV ? ? ? ? + ?

Nitrergic noncholinergic

+ Reflex bronchoconstriction Airway smooth muscle + Cholinergic nonnitrergic (purinoreceptor-)?

+ Airway ganglion

Figure 3 Innervation of NEB in rat lung. Schematic representation of possible interactions between purines, nerve terminals, and complex NEB receptors in the rat lung. The center of the scheme represents a pulmonary NEB (colored yellow) and its extensive interactions with nerve terminals. The upper left part shows the vagal afferent (nodose red neurons; jugular ochre neurons) and preganglionic parasympathetic efferent (colored lilac) connections; the bottom part shows a postganglionic parasympathetic ganglion of the airway wall (cholinergic neurons purple; nitrergic neurons green) and the upper right part shows dorsal root afferents (blue neurons). Another population of neurons intrinsic to the airway wall, located immediately beneath the epithelium, is represented in the right middle part of the scheme, close to the base of the NEB, and shows a nitrergic neuron (colored green) that innervates the NEB. Furthermore, all characterized nerve ber populations that are important for the present overview are included (color-coded). Known characteristics of the NEB and of the represented neuronal populations are included in the scheme in the same color as the respective structures. 5HT, serotonin; ACh, acetylcholine; BV, blood vessel; CALC, calcitonin; DRG, dorsal root ganglia; NTS, nucleus of the solitary tract. Reproduced from Adriaensen D and Timmermans JP (2004) Purinergic signalling in the lung: important in asthma and COPD? Current Opinion in Pharmacology 4: 207214, with permission from Elsevier.

154 NEUROPHYSIOLOGY / Neuroendocrine Cells

Airway epithelium Pulmonary NE cells Type II cell O2 sensor K+ 5-HT2cR

Ca2+

GRP, 5-HT, CGRP

3 KGF, CRF

EGF PDGF

3 GRP-R

Mesenchyme
Figure 4 Role of NE cells in lung development. Schematic diagram of the proposed role of NE cells and their peptide and amine products (GRP/5HT) in developing lung. The schema indicates that pulmonary NE cells release GRP/5HT (1) when stimulated by hypoxia as modulated through the O2 sensor. 5HT in turn also acts on type II cells (2), which express the serotonin receptor-HT2cR. GRP can act on the lung mesenchyme, which expresses the GRP receptor (GRP-R) and in turn stimulates mesenchymal cells to release epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) (3), which modulate epithelial cell functions, thereby completing the epithelialmesenchymal interaction (4). Mesenchyme, stimulated by GRP, will release keratinocyte growth factor (KGF) and corticotropin releasing factor (CRF) (3), which can further inuence development of type II cells (alveolar compartment). Since NE cells start functioning early during lung development, they are viewed as important modulators of lung organogenesis. Modied from Sunday ME and Cutz E (2000) Role of neuroendocrine cells in fetal and post natal lung. In: Mendelson CR (ed.) Endocrinology of the Lung: Development and Surfactant Synthesis, pp. 299336. Totowa: Humana Press.

in vivo promoted proliferation of both mesenchymal and epithelial cells in conducting airways and in primitive alveoli, increased branching morphogenesis, and induced differentiation of alveolar type II cells (Figure 4). These effects are directly related to the expression of GRP-preferring receptors widely distributed in the lung parenchyma. In addition to growth factor-like properties, bombesin/GRP-like peptides exhibit a variety of biological and pharmacological activities including constrictor effects in various smooth muscle preparations.
Function of NEB as Airway Chemoreceptors

suggested that NEBs function as hypoxia-sensitive airway chemoreceptors modulated by the CNS.
Cellular and Molecular Mechanisms of Oxygen Sensing

Morphological features consistent with a chemoreceptor function include: (1) preferential location at airway branch points, ideally positioned to monitor airway gas concentration; (2) the presence of amine and peptide neurotransmitters that are released upon hypoxia stimulus; and (3) vagal sensory innervation transmitting hypoxia signal to the central nervous system (CNS). In whole animal studies, Lauweryns and co-workers demonstrated degranulation and release of amine from NEB cells in lungs of rabbit neonates exposed to acute airway hypoxia, and

Electrophysiological studies have conrmed the role of NEB cells as airway O2 sensors and the actual transducers of hypoxia stimulus. Whole cell patch-clamp studies using cultures of NEBs isolated from rabbit fetal lung have demonstrated the presence of voltageactivated Na , Ca2 , and K currents, a key feature of excitable cells. Hypoxia (PO2 2530 mmHg) reversibly inhibited the outward K current in NEB cells while the inward Na and Ca2 were unaffected. Under current clamp conditions, hypoxia caused an increase in the slope and frequency of the depolarizing pacemaker potential. Hence, it was conrmed that NEB cells express a hypoxia-sensitive K (O2) current similar to that identied in other O2 sensing cells, namely the carotid body (CB) glomus cells, pulmonary artery myocytes, and certain neurons in the brain. The primary event in NEB O2 sensing in response to airway hypoxia is the closure of the O2-sensitive K channel. The actual O2 sensor is represented by a

NEUROPHYSIOLOGY / Neuroendocrine Cells 155

heme-linked NADPH oxidase closely associated with an O2-sensitive K channel. Under normoxia, the oxidase tonically generates superoxide from ambient O2, which is then rapidly converted to hydrogen peroxide (H2O2); this in turn modulates O2-sensitive K channel activity. Hypoxia decreases the level of H2O2 production resulting in K channel closure and NEB cell membrane depolarization. This then causes activation of voltage-sensitive Ca2 channels with inux of extracellular Ca2 triggering exocytosis of DCVs and release of neurotransmitters (i.e., 5-HT). NADPH oxidase is the principal O2 sensor in NEB cells since mice with oxidase deciency (OD, gp91phox k/o) show no response to acute hypoxia. Furthermore, neonatal OD mice show abnormal breathing and fail to respond to acute hypoxia challenge when assessed by whole body plethysmography. On the other hand, the CB function and pulmonary artery responses to hypoxia in the same OD mice appear intact, suggesting alternate O2 sensing mechanisms.
Chemotransmission of Hypoxia Stimulus

The candidates for neurotransmitters that mediate fast chemosensory transmission of hypoxia stimulus from NEB cells via vagal sensory afferents include 5HT, acetylcholine (ACh), and adenosine triphosphate (ATP). Evidence in support of 5-HT as a transmitter of hypoxia stimulus include in vivo and in vitro studies in the rabbit model as well as recent investigation using carbon ber amperometry. These studies have shown that hypoxia causes dose-dependent 5-HT release from NEB within the physiologic range expected in the airway (i.e., PO2 o95 mmHg). NEB cells express a 5-HT 3 receptor acting as an autoreceptor with positive feedback and amplication of hypoxia signaling. The evidence for cholinergic mechanisms in NEB includes demonstration of acetycholinesterase activity, the presence of small clear vesicles in efferent-like nerve endings in contact with NEB cells, and immunohistochemical demonstration of vesicular acetylcholine transporter (VChat) activity. NEB cells also express functional nicotinic acetylcholine (nACh) receptors, which are critical in mediating the effects of nicotine derived from smoking. The possible involvement of ATP and purinergic mechanisms is based on the demonstration of ATP in NEB cells and expression of P2/X receptors in nerve endings innervating NEBs as well as on NEB cells proper. Heteromeric P2X2/3 receptors in NEB cells possibly function as autoreceptors involved in modulation of hypoxia chemotransmission and other stimuli.
Neuroendocrine Cells in Respiratory Diseases

Abnormalities in the number and distribution of NE cells/NEB have been documented in various pediatric

lung disorders, as well as in adults with a variety of chronic interstitial lung diseases and in lung carcinogenesis. Increased numbers of NE cells/NEBs have been reported in lungs of infants with lung hypoplasia due to diaphragmatic hernia. The proposed mechanisms include compensatory increase related to impaired lung growth and/or failure of neuropeptide release during neonatal adaptation. Signicant hyperplasia of bombesin/GRP immunoreactive NE cells/NEBs has been reported in cases of bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants characterized by ongoing airway epithelial injury and repair. Although the precise mechanism is not known, chronic hypoxia and/or release of inammatory cytokines could stimulate mitogenesis of NE cells/NEBs or recruitment from precursor cell. Infants with BPD exhibit a number of physiological abnormalities (i.e., airway hyperreactivity, pulmonary hypertension, and increased apneic spells) possibly related to NE cells/ NEB hyperplasia and increased levels of pulmonary bombesin/GRP. Hyperplasia of NE cells/NEBs has also been described in congenital central hypoventilation syndrome and in sudden infant death syndrome (SIDS), both disorders characterized by dysfunction in respiratory control. In cases of SIDS there is marked hyperplasia of NE cells/NEBs, especially in lungs of infants whose mothers smoked during pregnancy. In this situation the proliferation of these cells is likely driven via nACh-receptors as demonstrated in several animal models exposed to cigarette smoke or nicotine. Possible dysfunction of NE cells/NEBs has been implicated in the pathogenesis of cystic brosis (CF) since these cells express cystic brosis transmembrane regulator (CFTR). Experimental data suggest that normal CFTR function is required for O2 sensing and for amine/peptide secretion by NE cells/NEBs, which in turn may affect the composition of pericilliary uid eventually leading to thickened mucus accumulation and airway plugging. The lung diseases in adults associated with NE cell/ NEB hyperplasia encompass both benign and neoplastic conditions including usual interstitial pneumonitis, eosinophilic pneumonitis, idiopathic pulmonary NE cells hyperplasia, carcinoid tumors, and small cell lung carcinoma (SCLC). The possible mechanisms include interactions of inammation, cytokines, smoking and hypoxia-activating neurogenic gene (Hash-1) expression, and mitogenic pathways. In SCLC a bombesin/GRP autocrine growth mechanism drives tumor cell proliferation, hence a potential therapy using peptide antagonists is being actively pursued. Presently, there are no specic therapies that target NE cell/NEB dysfunction.

156 NEUROPHYSIOLOGY / Neurons and Neuromuscular Transmission See also: Cystic Fibrosis: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene. Lung Development: Overview. NADPH and NADPH Oxidase.
nuclei, which in turn supply respiratory muscles in the thorax, abdomen, and upper airway. Neuromuscular transmission is the process by which motoneuronal activation results in muscle contraction. An action potential is propagated from the motoneuronal cell body down the axon to the nerve terminal. The depolarization opens voltage-gated calcium channels, elevating intracellular calcium concentrations. Acetylcholine is stored in vesicles at the nerve terminal. Vesicle docking requires the generation of the synaptic fusion complex, in which SNARE proteins play key roles. Exocytosis stimulated by elevated calcium levels releases acetylcholine into the synaptic cleft. When two acetylcholine molecules bind to a postjunctional acetylcholine receptor, the cation channel of the receptor opens, depolarizing the cell. If sufcient transmitter is released, the depolarization will initiate an action potential in the muscle cell, eliciting contraction via a cascade of electrophysiological and biochemical events. Acetylcholinesterase terminates the action of acetylcholine, and transmitter is then recycled by reuptake into the nerve terminal. Impairment of neuromuscular transmission can occur during high-intensity and -duration activation in normal neuromuscular junctions or as a result of specic perturbations caused by diseases such as myasthenia gravis and botulism.

Further Reading
Adriaensen D, Brouns I, Van Genechten J, and Timmermans JP (2003) Functional morphology of pulmonary neuroepithelial bodies: extremely complex airway receptors. Anatomical Record 270A: 2540. Adriaensen D and Timmermans JP (2004) Purinergic signalling in the lung: important in asthma and COPD? Current Opinion in Phamacology 4: 207214. Cutz E, et al. (1995) Pulmonary neuroendocrine system: an overview of cell biology and pathology with emphasis on pediatric lung disease. Perspectives in Pediatric Pathology 18: 3270. Cutz E (ed.) (1997) Cellular and Molecular Biology of Airway Chemoreceptors. Austin: Landes Bioscience. Cutz E, Fu XW, Yeger H, et al. (2003) Oxygen sensing in pulmonary neuroepithelial bodies and related tumor cell models. In: Lahiri S, Semenza GL, and Prabhakar NR (eds.) Oxygen Sensing Responses and Adaptation to Hypoxia, Lung Biology in Health and Disease, vol. 175, pp. 567602. New York: Dekker. Cutz E and Jackson A (1999) Neuroepithelial bodies as airway oxygen sensors. Respiratory Physiology 115: 201214. Cutz E and Jackson A (2001) Airway inammation and peripheral chemoreceptors. In: Bayard RW and Krous HF (eds.) Sudden Infant Death Syndrome: Problems, Progress and Possibilities, pp. 156180. London: Arnold. Gosney JR (1992) Pulmonary Endocrine Pathology. Oxford: Butterworth Heinemann. Ito T, Udaka N, Okudela K, et al. (2003) Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma. Endocrine Pathology 14: 133139. Sunday ME (1997) Neuropeptides and lung development. In: McDonald JE (ed.) Lung Growth and Development. Lung Biology in Health and Disease, vol. 100, pp. 401494. New York: Dekker. Sunday ME and Cutz E (2000) Role of neuroendocrine cells in fetal and post natal lung. In: Mendelson CR (ed.) Endocrinology of the Lung: Development and Surfactant Synthesis, pp. 299 336. Totowa: Humana Press. Van Lommel A, Bolle T, Faunes W, and Lauweryns JM (1999) The pulmonary neuroendocrine system: the past decade. Archives of Histology and Cytology 62: 116. Youngson C, Nurse CA, Yeger H, and Cutz E (1993) Oxygen sensing in airway chemoreceptors. Nature 365: 153155.

Description
The respiratory motor system maintains ventilatory homeostasis during rest and exercise and also in response to a variety of environmentally and diseaseinduced perturbations. It is composed of several key elements. At the level of the brain, neuronal groups located primarily in the medulla and pons are responsible for the generation and modulation of the respiratory rhythm and for integrating sensory information. These project to the spinal cord and cranial motor nuclei, where respiratory motoneurons send axons to inspiratory and expiratory muscles of the thorax, abdomen, and upper airways. In the periphery, motoneurons transmit information to the skeletal muscles via the neuromuscular junction (Figure 1). In the mammalian respiratory system, each motoneuron supplies several muscle bers, and each muscle ber is supplied by one motoneuron. The motoneuron and the muscle bers it supplies comprise the motor unit, which forms the cellular basis for the regulation of respiratory muscle contraction. Muscles involved in breathing are a heterogeneous group with respect to anatomic location, size, mechanical action, ber-type composition, biochemical properties, and contractile performance. During low to moderate levels of activation, transmission from motoneuron to muscle has complete delity. As a result, the mechanical output of the muscle depends directly on the ring pattern of each motoneuron and the contractile response of each muscle ber to that pattern of activation. Neuromuscular transmission has a high safety factor in that considerably more acetylcholine is released than required to ensure muscle ber contraction. However, high-intensity

Neurons and Neuromuscular Transmission

E van Lunteren, Case Western Reserve University, Cleveland, OH, USA
& 2006 Elsevier Ltd. All rights reserved.

Abstract
Brain neurons that generate and modulate respiratory rhythms are located predominantly in the medulla and pons. They activate motor neurons located in the spinal cord and cranial nerve