Immunhistochemische Studien zur fetalen Entwicklung der Innervation und der Verteilung neuroendokriner Zellen und neuroepithelialer Körperchen in der menschlichen Lunge.

The aim of the present study was to investigate the origin of neuroendocrine cells and neuroepithelial bodies in the human fetal lung as well as the develpoment of their innervation patterns. Embryos and fetuses of a crown-rump measurement of 30 mm to 110 mm were stained following standard immunohistochemical protocols using primary antibodies against markers of neuroendocrine cells (chromogranin(Cg)A, PGP 9.5,bombesin) as well as peripheral nerves (PGP 9.5). Histological sections were analyzed qualitatively. In the epithelium of small bronchioli, bombesin-positive neuroendocrine cells could be detected earlier than CgA positive neuroendocrine cells. At later time points, immunopositive cell clusters surrounding the bronchi as well as bronchioli in the lungs parenchym could be identified while the number of neuroendocrine cells in the epithelium decreased. Neuroepithelial bodies could not be detected within the epithelium by any of the tested antibodies. Using PGP 9.5 primary antibody, no individual neuroendocrine cells could be detected in the lungs stroma. However, clusters of PGP 9.5 positve cells were identified within the stroma. In the present study, it was impossible to determine if these later clusters were indeed extraepithelial neuroendocrine bodies or peribronchial ganglia. Individual nerve fibers within the lungs stroma could be detected as early as in an 30 mm embryo, suggesting that neuronal tissue invades into the lung early. Later in development, perobronchial ganglia appeared. The present study failed to identify direct connections between the invading nerve fibers and the neuroendocrine cells in the epithelium. Presence of cholinergic innervation of the lung can be detected using antibodies directed against VMAT and VAChT. A definitive clarification of the origin of the lungs neuroendocrine cells could not be achieved in the present study. Neither the autochthone theory of origin nor the neural crest theory could be ruled out with the presented data. Further studies on lungs of earlier embryonic development stages are needed to determine if neuroenocrine cells are preceding other elements of nervous system. The presence of extraepithelial immunopositive cell clusters in this study raises the question whether these are a new species of extraepithelial neuroendocrine bodies. Further studies investigating these cells are needed.