Pulmonary Neuroendocrine Cell System Research Articles

Incidental postmortem diagnosis of DIPNECH in a patient with previously unexplained ‘asthma bronchiale’

We report the case of a 69-year-old female patient with a progressively worsening, clinically unexplained symptomatic asthma bronchiale who eventually died due to urosepsis. A subsequent autopsy revealed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a very rare preneoplastic disease of the pulmonary neuroendocrine cell system, as the cause of asthma bronchiale in our patient. We hypothesize that DIPNECH may be an underestimated cause of obstructive lung disease in a certain subset of patients. Therefore, studies are warranted to obtain statistically reliable demographic and clinical data of this pulmonary condition. Moreover, this case strongly argues for the relevance and significance of non-forensic autopsies in the clinical setting.

Pulmonary Neuroendocrine Cell System in Health and Disease

Pulmonary neuroendocrine cell (PNEC) system consists of solitary cells and innervated clusters, neuroepithe- lial bodies (NEB), widely distributed throughout the airway mucosa of mammalian lungs. These cells are numerous in fe- tal/neonatal lungs and produce amine (serotonin, 5-HT) as well as a variety of neuropeptides (e.g. bombesin). The poten- tial role and significance of these highly specialized lung cells in normal and diseased lung is only now beginning to be appreciated. The multifaceted role(s) of PNEC system include lung development, neonatal adaptation and during postnatal airway homeostasis as guardians of stem cell niche. Recent advances in cellular and molecular biology of PNEC system particularly their ontogeny and mechanisms of neuroendocrine differentiation in developing lung are reviewed. The evidence for the role of NEB as hypoxia-sensitive airway chemoreceptors is presented including identification and characterization of O2 sensor molecular complex that is activated by hypoxia leading to release of amine and peptide me- diators acting locally or via NEB neural connections. Thus NEB are postulated to function as O2 sensitive airway sensors involved in respiratory control, especially during adaptation to extrauterine life. Hyperplasia of PNEC/NEB cells, suggest- ing altered function, has been identified in a number of perinatal/pediatric lung disorders including bronchopulmonary dysplasia, central hypoventilation syndrome, Sudden Infant Death Syndrome and Neuroendocrine Hyperplasia of Infancy as well as Cystic Fibrosis and pediatric asthma. In the adults, PNEC/NEB may be involved in the pathogenesis of tobacco induced airway disease, pulmonary fibrosis and lung carcinogenesis.

Pulmonary neuroendocrine cell system in pediatric lung disease-Recent advances

Pulmonary neuroendocrine cell system in pediatric lung disease-Recent advances

Innervation of pulmonary neuroendocrine cells and neuroepithelial bodies in developing rabbit lung.

We investigated the development of innervation of the pulmonary neuroendocrine cell (PNEC) system composed of single cells and organoid cell clusters, neuroepithelial bodies (NEB) in rabbit fetal and neonatal lungs. To visualize the nerve fibers and their contacts with PNECs/NEBs, we used confocal microscopy and multilabel immunohistochemistry (IHC) with pan-neural marker, synaptic vesicle protein 2 (SV2), and serotonin (5-HT) as markers for PNECs/NEBs, and smooth muscle actin or cytokeratin to identify airway landmarks. The numbers and distribution of PNEC/NEB at different stages of lung development (E16, 18, 21, 26, and P2) and the density of innervation were quantified. First PNECs immunoreactive for 5-HT were identified in primitive airway epithelium at E18 as single cells or as small cell clusters with or without early nerve contacts. At E21 a significant increase in the number of PNECs with formation of early innervated NEB corpuscules was observed. The overall numbers of PNECs/NEBs and the density of mucosal, submucosal, and intercorpuscular innervation increased with progressing gestation and peaked postnatally (P2). At term, the majority of NEBs and single PNECs within airway mucosa possessed neural contacts. Such an extensive and complex innervation of the PNEC system indicates a multifunctional role in developing lung and during neonatal adaptation.

CD56: a useful marker for diagnosing Merkel cell carcinoma

Background: Merkel cell carcinoma (MCC) of the skin is an aggressive but rare malignant neuroendocrine tumor. For its pathological diagnosis, we use a panel of immunohistochemical markers, such as cytokeratin 20 (CK 20), epithelial membrane antigen (EMA), chromogranin A, neuron specific enolase (NSE), synaptophysin, and Leu7 (CD57) to demonstrate its epithelial and neuroendocrine features. CD56, or neural cell adhesion molecule (NCAM), has been demonstrated recently as the tumor marker of the pulmonary neuroendocrine cell system. Its expression in MCC, however, has still rarely been investigated. Furthermore, in such very few previous studies on NCAM expression in MCC, all the tumor cells were not necessarily demonstrated to express NCAM. Objectives: To study the immunoreactivity of CD56 in MCC, especially using a monoclonal antibody of a clone 1B6, different from those adopted in the previous reports. Methods: We reexamined CD56 expression immunohistochemically in five MCC cases, along with the conventional panel of markers described above, using paraffin-embedded tissue sections. Results: CD56 revealed the most diffuse and intense positive staining, which was noted along the cell borders, in all specimens compared with other neuroendocrine tumor markers. Conclusions: The results of our study indicate that CD56, especially a new monoclonal antibody (clone 1B6), is a useful immunohistochemical marker for MCC.

Expression of CFTR and Cl(-) conductances in cells of pulmonary neuroepithelial bodies.

The pulmonary neuroendocrine cell system comprises solitary neuroendocrine cells and clusters of innervated cells or neuroepithelial bodies (NEBs). NEBs figure prominently during the perinatal period when they are postulated to be involved in physiological adaptation to air breathing. Previous studies have documented hyperplasia of NEBs in cystic fibrosis (CF) lungs and increased neuropeptide (bombesin) content produced by these cells, possibly secondary to chronic hypoxia related to CF lung disease. However, little is known about the role of NEBs in the pathogenesis of CF lung disease. In the present study, using a panel of cystic fibrosis transmembrane conductance regulator (CFTR)-specific antibodies and confocal microscopy in combination with RT-PCR, we demonstrate expression of CFTR message and protein in NEB cells of rabbit neonatal lungs. NEB cells expressed CFTR along with neuroendocrine markers. Confocal microscopy established apical membrane localization of the CFTR protein in NEB cells. Cl(-) conductances corresponding to functional CFTR were demonstrated in NEB cells in a fresh lung slice preparation. Our findings suggest that NEBs, and related neuroendocrine mechanisms, likely play a role in the pathogenesis of CF lung disease, including the early stages before establishment of chronic infection and chronic lung disease.

Pulmonary neuroendocrine cell system in pediatric and adult lung disease.

In humans lungs affected by naturally occurring pulmonary disease, the pulmonary neuroendocrine cell system, which is normally arranged in a sparse but even distribution throughout the respiratory tract, increases in size. It is likely that the stimulus for this is pulmonary injury and that its purpose is the paracrine regulation of the restoration of pulmonary tissues to their normal state, an hypothesis supported by studies of animal lungs subjected to experimental injury as well as of the development of human and animal lungs in utero. Initially, this increase involves the development of interrupted rows of neuroendocrine cells. In the later stages, however, development of more disorderly intraepithelial aggregates can occur and the small, locally invasive neuroendocrine cell lesions known as tumourlets may occasionally result. Both of these latter structures often contain secretory products not found in the neuroendocrine cells of normal human lungs, probably indicating a derangement of what appears to be a fundamentally physiological response. It is likely that, in some circumstances, this disorderly change may contribute to pulmonary disease as well as being the result of it.

Comparative histology of pulmonary neuroendocrine cell system in mammalian lungs

Comparative histology of pulmonary neuroendocrine cell system in mammalian lungs

Serotonin-like immunoreactive cells in the pulmonary epithelium of ancient fish species

The pulmonary mucosa of three species of ancient fish was studied immunohistochemically to show the distribution of serotonin, regarded as the main monoamine of mammalian bronchopulmonary paraneurons. Serotonin-like immunoreactive cells, dispersed through the airway epithelium as single cells, were found in all the fish species studied. They are presumably equivalent to the neuroendocrine cells reported in the lungs of mammalian and submammalian vertebrates. However, the precise role and the function of these cells remain unknown. Since the species studied belong to the most primitive extant groups of ancient fish, the present investigation suggests that serotonin is widely distributed in the lungs of the vertebrates. Several peptides, known to be specific cytochemical markers for the identification of the pulmonary neuroendocrine cells of mammals, are being investigated in the lungs of the fish species studied. They may help to trace the phylogeny of the pulmonary neuroendocrine cell system and to elucidate its function in lower vertebrates.