Innervated groups of neuroendocrine cells, called neuroepithelial bodies (NEBs), are diffusely spread in the epithelium of intrapulmonary airways in many species. Our present understanding of the morphology of NEBs in mammalian lungs is comprehensive, but none of the proposed functional hypotheses have been proven conclusively. In recent reviews on airway innervation, NEBs have been added to the list of presumed physiological lung receptors. Microscopic data on the innervation of NEBs, however, have given rise to conflicting interpretations. Using neuronal tracing, denervation, and immunostaining, we recently demonstrated that the innervation of NEBs is much more complex than the almost unique vagal nodose sensory innervation suggested by other authors. The aim of the present work is to summarize our present understanding about the origin and chemical coding of the profuse nerve terminals that selectively contact pulmonary NEBs. A thorough knowledge of the complex interactions between the neuroendocrine cells and at least five different nerve fiber populations is essential for defining the position Key words: NEBs; neuroepithelial bodies; innervation; airway receptors; lung; rat Highly specialized neuroepithelial bodies (NEBs) , which consist of extensively innervated groups of pulmonary neuroendocrine cells (PNECs), are normal components of the epithelium of intrapulmonary airways in humans, mammals, and all air-breathing vertebrate species investigated so far.The pulmonary neuroendocrine system was first reported more than 50 years ago (Fröhlich, 1949), but especially over the last 25 years detailed information has been provided about the distribution, ontogeny, and microscopic morphology of NEBs (for reviews see Scheuermann, 1987;Sorokin and Hoyt, 1989;Adriaensen and Scheuermann, 1993;Sorokin et al., 1997).PNECs belong to the diffuse neuroendocrine system (DNES) (Pearse and Takor Takor, 1979), members of which have been assigned important roles in the peripheral control of various organs. The pulmonary DNES in healthy lungs appears to be characterized by the production of amines and several neuropeptides, including serotonin (5-HT), bombesin (gastrin-releasing peptide), calcitonin gene-related peptide (CGRP), calcitonin, enkephalin, somatostatin, cholecystokinin, and substance P (SP) (for reviews see Sorokin and Hoyt, 1989; Scheuermann et al., 1992;Adriaensen and Scheuermann, 1993). These bioactive substances are stored in secretory granules (60 -200 nm diameter) with typical endocrine-like characteristics, the so-called dense-cored vesicles (DCVs).Interestingly, PNECs are by far the first cell type to fully differentiate in the human airway epithelium (before

The characteristics of the different populations of sensory nerve terminals that selectively contact pulmonary neuroepithelial bodies (NEBs) in rat lungs were investigated after chemical denervation with capsaicin and compared with control lungs. Vagal calbindin D28k and P2X(3) purinoceptor immunoreactive (IR) afferent nerve terminals contacting NEBs appeared to have their origin in the nodose ganglion. Thick CB/P2X(3)-IR nerve fibers were seen to be myelinated and to lose their myelin sheaths just before branching and protruding intraepithelially between the NEB cells. This vagal sensory component of the innervation of NEBs was not affected by capsaicin nor expressed capsaicin receptors (vanilloid receptor subtype 1). A second sensory nerve fiber population that selectively innervates pulmonary NEBs in the rat lung consists of thin unmyelinated nonvagal substance P/calcitonin gene-related peptide IR nerve fibers, contacting mainly the basal pole of pulmonary NEBs, and having their origin in dorsal root ganglia. In concordance with vanilloid receptor 1 expression on these nerve terminals, the spinal sensory substance P/calcitionin gene-related peptide-IR component of the innervation of NEBs was depleted by systemic capsaicin treatment. The complex sensory innervation pattern of pulmonary NEBs characterized in the present study strongly suggests that, physiologically, pulmonary NEBs represent a group of intraepithelial receptors that may be able to accommodate various local and central reflex actions, in relation to both chemo- and mechanosensory stimuli.