Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease

Abstract

Mammalian lungs have the ability to recognize external environments by sensing different compounds in inhaled air. Pulmonary neuroendocrine cells (PNECs) are rare, multi-functional epithelial cells currently garnering attention as intrapulmonary sensors; PNECs can detect hypoxic conditions through chemoreception. Because PNEC overactivation has been reported in patients suffering from respiratory diseases – such as asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia and other congenital diseases – an improved understanding of the fundamental characteristics of PNECs is becoming crucial in pulmonary biology and pathology. During the past decade, murine genetics and disease models revealed the involvement of PNECs in lung ventilation dynamics, mechanosensing and the type 2 immune responses. Single-cell RNA sequencing further unveiled heterogeneous gene expression profiles in the PNEC population and revealed that a small number of PNECs undergo reprogramming during regeneration. Aberrant large clusters of PNECs have been observed in neuroendocrine tumors, including small-cell lung cancer (SCLC). Modern innovation of imaging analyses has enabled the discovery of dynamic migratory behaviors of PNECs during airway development, perhaps relating to SCLC malignancy. This Review summarizes the findings from research on PNECs, along with novel knowledge about their function. In addition, it thoroughly addresses the relevant questions concerning the molecular pathology of pulmonary diseases and related therapeutic approaches.

Molecular crosstalk in tracheal development and its recurrence in adult tissue regeneration

“…(See our review papers for more detailed information on the roles of Notch signaling 78 and neuroendocrine cells 79 in the mammalian respiratory system)…”

WNT Signalling in Lung Physiology and Pathology

“…Studies using single-cell RNA-sequencing and numerous genetically engineered mouse models of specific lung cancer subtypes have suggested that distinct lung epithelial progenitor cells may undergo malignant transformation in lung cancer subtypes. For instance, neuroendocrine cells were shown to form SCLC tumor with Tp53 and Rb knockout (Leeman et al 2014;Song et al 2012;Noguchi et al 2020). Further, both BASC and ATII cells were demonstrated to contribute to Krasactivated ADC (Leeman et al 2014;Kim et al 2005;Xu et al 2012).…”

Not Only COVID-19: Involvement of Multiple Chemosensory Systems in Human Diseases

“…Pulmonary neuroendocrine cells are a small percentage (less than 1%) of pulmonary epithelial cells, innervated by the vagus nerve ( Noguchi et al, 2020 ). They sense oxygen through a NADPH oxidase coupled to a potassium channel sensitive to oxygen.…”

“…They sense oxygen through a NADPH oxidase coupled to a potassium channel sensitive to oxygen. They may sense multiple chemical parameters from hypoxia to air pollutants in bronchial air (for example nicotine sensing through nicotinic Ach receptors), secrete serotonin, other peptides, and also ATP, which acts on autoreceptors and nerve terminals’ P2X receptors, and are involved in regulating Type 2 immune response ( Noguchi et al, 2020 ). They amplify allergic asthma responses ( Sui et al, 2018 ) via a neuroimmune mechanism ( Pavón-Romero et al, 2021 ), yet mitigate hypoxic injury ( Shivaraju et al, 2021 ).…”