Neuroepithelial bodies as airway oxygen sensors

Abstract

Since the discovery of neuroepithelial bodies (NEB) in the late 1930s, evidence has accumulated to suggest that these cells may function as hypoxia-sensitive airway sensors. Until recently, this hypothesis was based largely on morphological observations. The use of in vitro models of isolated NEB, combined with electrophysiological approaches, have provided direct evidence that NEB cells express a membrane-bound O₂ sensor and are the transducers of hypoxic stimulus. Here, we review the historical evidence and current state of knowledge of the oxygen-sensing properties of NEB cells, comparison with other O₂ sensing cells, as well as recent advances that have been made using molecular and electrophysiological techniques. The possible role of NEB in perinatal pulmonary pathophysiology is also discussed.

Introduction

Over 50 years ago, the existence of solitary and grouped cells with a clear cytoplasm and ‘neuroendocrine’ characteristics, widely dispersed throughout the airway epithelium of mammals, were discovered in mammalian lungs. In the early seventies, Lauweryns and Peuskens designated innervated clusters of these cells as intrapulmonary neuroepithelial bodies (NEB) (Lauweryns and Cokelaere, 1973). These innervated epithelial corpuscles have since been characterized in the lungs of humans, various mammals and amphibians (Cutz et al., 1984, Cutz et al., 1995, Sorokin and Hoyt, 1989, Adriaensen and Scheuermann, 1993). In a series of experiments using rabbit neonates, Lauweryns and colleagues have shown that NEB react to airway hypoxia by increased exocytosis of its dense core vesicles and decrease in cytoplasmic amine content, suggesting that these cells may represent hypoxia-sensitive airway sensors (Lauweryns and Cokelaere, 1973, Lauweryns et al., 1977, Lauweryns et al., 1978). It has been estimated that NEB represent <1% of epithelial cells in human lungs (Cutz et al., 1984). This relatively small number of NEB and widespread distribution in a complex organ with difficult access has slowed our progress in unraveling their precise function. Given these obstacles, the general consensus is that NEB may function as hypoxia-sensitive airway sensors, and together with the principal arterial chemoreceptor (i.e. the carotid body), initiate sensory inputs to affect the control of respiration.

Sorokin and Hoyt, 1989, Sorokin and Hoyt, 1990 have previously discussed some of the supposed functions of NEB in mammalian lungs including: (1) the ability of NEB to function as transducers, i.e. they translate the airway ‘chemical’ environment (e.g. hypoxia) into a change in electric current by releasing mediators at the basal pole; (2) modulation of bronchomotor tone via targeting bronchial smooth muscle and the associated nerves located directly beneath NEB; (3) promotion and regulation of the growth of developing airways by stimulating the proliferation of local endoderm; (4) release of amine and peptide modulators in response to increasing fetal hypoxia near term in order to maintain vasoconstriction in the pulmonary circuit; and (5) neonatal respiratory adaptation. Here we briefly overview the structural and functional data as well as recent cellular and molecular studies on O₂-sensing properties of NEB cells. The possible involvement of NEB in the pathophysiology of some neonatal/pediatric pulmonary disorders is also discussed.