© 2003 American Thoracic Society DOI: 10.1165/rcmb.F261
Lung SensorsComplex Functions Require Complex StructuresAnatomy Institute, University of Erlangen-Nuremberg, Germany Address correspondence to: Prof. Dr. med. W.L. Neuhuber, Universität Erlangen-Nürnberg, Anatomisches Institut, Vorstand Lehrstuhl I, Krankenhausstraße 9, D-91054 Erlangen, Germany. E-mail: winfried.neuhuber{at}anatomie1.med.uni-erlangen.de
Abbreviations: calcitenin gene-related peptide, CGRP • neuroepithelial bodies, NEB The regulation of bodily functions is achieved by the sophisticated interplay of nervous and endocrine systems. Although current textbooks of physiology suggest a fairly detailed understanding of most mechanisms, significant gaps in our knowledge become evident on closer scrutiny. One of the most enigmatic structures in the respiratory system are neuroepithelial bodies (NEB) occurring in the lungs of virtually all vertebrates studied thus far (1). Both structural and functional studies over the past 3 decades have suggested a chemosensory function responding to hypoxia with the release of bioactive substances (e.g., serotonin and calcitenin gene-related peptide [CGRP]) (2, 3). Thus, NEB presumably carry out significant functions in both physiology and pathophysiology of the cardiopulmonary system. An important factor indispensable for a full acknowledgment of their functional significance (i.e., their innervation) was poorly known until recently. Vagal afferent innervation, as demonstrated by vagotomy experiments (4), appeared compatible with chemosensor function similar to the carotid body. However, it was not until the studies published by Dirk Adriaensen and colleagues that the full complexity of NEB innervation was elucidated. In their most recent article published in this issue of the AJRCMB, Brouns and colleagues (5) were able to disentangle vagal and spinal afferent fibers providing dual sensory innervation to NEB. This was achieved by combining sophisticated multilabel immunocytochemistry, confocal laser scanning microscopy, and pharmacologic nerve ablation using capsaicin. It turned out that a majority of NEB is innervated by vagal afferents derived from thick myelinated axons that penetrate, after having lost their myelin sheaths, between the neuroepithelial cells. These vagal afferents displayed immunoreactivity for calbindin and purinergic P2X3 receptors, but were negative for the vanilloid receptor 1. Some of these neurochemical features were already described and related to a vagal afferent nature by both vagotomy and retrogade tracing in a previous article by the same authors (6). Anterograde tracing from the nodose ganglion also revealed vagal afferents protruding into NEB (7, 8). A second afferent fiber population converging onto the same NEB was immunoreactive for both CGRP/substance P and vanilloid receptor 1 and disappeared upon capsaicin treatment. These features are consistent with a dorsal root ganglionic origin. Interestingly, these spinal afferents formed a plexus beneath NEB without penetrating between epithelial cells (5, 6). There is even a third neuronal population contributing to NEB innervation (i.e., nitrergic intrapulmonary ganglionic neurons) (9). These intrinsic neurons are noncholinergic and provide dense intraepithelial terminals to NEB. Strikingly, their cell bodies are contacted by collaterals of CGRP immunoreactive spinal afferents. What might this complex innervation pattern be good for (Figure 1)? Reasonably, vagal afferents could perform a messenger role for brainstem networks regulating homeostasis by providing information about oxygen content of inhaled air, thus complementing arterial chemosensors. This idea is supported by a variety of both morphologic and functional findings (1, 5). However, the precise mechanisms still await elucidation. Demonstration of P2X3 receptor immunoreactivity in vagal afferent terminals is an important step and may point to a role for ATP released by NEB cells. Further immunocytochemical characterization of the equipment of identified vagal afferents with other receptor molecules is certainly a rewarding task for future studies. The role of spinal afferents is less obvious. Spinal afferents have been shown to respond to irritants (e.g., ammonia and cigarette smoke and may transmit nociceptive signals [10]). It is tempting to speculate that mediators released from NEB and acting on the subepithelial plexus of CGRP/substance P–positive spinal afferents are involved in these processes. In turn, spinal afferent endings may also release their peptide mediators, thus establishing local axon reflexes. A significant finding in this context is the innervation of intrapulmonary NO producing neurons by collaterals of CGRP-positive spinal afferents (9). Stimulation of spinal afferents may thus modulate activity of intrinsic nitrergic neurons which innervate NEB, thus influencing serotonin or CGRP release from NEB cells. There is ample opportunity for complex mutual interactions of NEB and their triple innervation.
However, the most intriguing idea put forward in the article in this issue of AJRCMB by Brouns and colleagues (5) relates to mechanosensation. Slowly and rapidly adapting mechanosensors in the respiratory system represent one of the most thorougly studied classes of primary afferent neurons (11, 12). Although there are good candidate structures for slowly adapting mechanosensors in smooth muscle of extrapulmonary airways (see REFERENCES in 11), this appears not to be the case for intrapulmonary sensors, nor for rapidly adapting sensors in particular. Anterograde tracing from the nodose ganglion revealed vagal afferent fibers within the lung concentrated on NEB leaving other areas virtually uninnervated (7, 8). Thus, vagal mechanosensory afferents should be found among the fibers labeled. In particular, vagal afferents leading to NEB were shown to be myelinated (5), as were both slowly and rapidly adapting vagal afferents, as characterized in numerous electrophysiologic studies (11, 12). Per exclusionem, at least part of vagal afferent fibers connected to NEB are favorable candidate structures for bronchopulmonary mechanosensors. This situation is reminiscent of the gastrointestinal tract, where anterograde tracing studies led to the acknowledgment of particular vagal afferent structures, the so-called intraganglionic laminar endings, as prime candidates for low-threshold muscular mechanosensors (13). Although somewhat odd at first glance, the idea that NEB, with their afferent innervation, may function as complex "corpuscular" mechanosensors is further fueled by the finding of P2X3 receptors in vagal afferent endings connected to NEB (5, 6). Mechanical stimulation may trigger release of ATP from NEB, thus exciting vagal afferents (Figure 1). These new data support older speculations on a mechanosensor role of NEB (5) and may initiate future functional studies. This set of recent studies by Brouns, Adriaensen and colleagues (5–7, 9), as well as by other groups, contributed important new information on the structural complexity of NEB and their innervation. They certainly represent seminal works, paving the way to an understanding of the variety of roles played by neuroendocrine cells in the respiratory system, 60 yr after they were discovered by Feyrter (1). Received in original form November 18, 2002
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