Differentiation and proliferation of pulmonary neuroendocrine cells.

In this review article the morphological profiles of pulmonary neuroendocrine cells (PNEC) in experimental animals and humans are described. Although the mechanisms of differentiation and proliferation of neuroendocrine cells in the airway epithelium remain to be solved, several experimental studies using explant culture and cell culture systems of fetal animal lungs have been performed to clarify fundamental phenomena associated with neuroendocrine differentiation and proliferation. Experimental animal studies using chronic hypoxia, toxic substances and carcinogens have succeeded in inducing alterations in PNEC systems, and these studies have elucidated the reactions of PNEC in cell injury and inflammation, and functional aspects of PNEC in disease conditions. Human pulmonary neuroendocrine tumors include various histological subtypes, and show divergent morphological and biological varieties. Molecular abnormalities of small cell carcinoma, the most aggressive subtype of pulmonary neuroendocrine tumors, have been extensively studied, but the mechanism of neuroendocrine differentiation of this tumor is still largely unknown. PNEC share common phenotypes with neuronal cells, and developmental studies have begun contributed evidence that similar transcriptional networks, including active and repressive basic helix-loop-helix (bHLH) factors, function in the differentiation of both PNEC and neuronal cells. Such a bHLH network may also play a central role in determining cell differentiation in lung carcinomas. Further studies of the neuronal bHLH network, its regulatory system and related signal transduction pathways, will be required for understanding the mechanisms of neuroendocrine differentiation and proliferation in normal and pathological lung conditions.