Excess neuropeptides in lung signal through endothelial cells to impair gas exchange

• Published in: Developmental cell Vol. 57; no. 7; pp. 839 - 853.e6
• Main Authors: Xu, Jinhao, Xu, Le, Sui, Pengfei, Chen, Jiyuan, Moya, Esteban A., Hume, Patrick, Janssen, William J., Duran, Jason M., Thistlethwaite, Patricia, Carlin, Aaron, Gulleman, Peter, Banaschewski, Brandon, Goldy, Mary Kate, Yuan, Jason X.-J., Malhotra, Atul, Pryhuber, Gloria, Crotty-Alexander, Laura, Deutsch, Gail, Young, Lisa R., Sun, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-04-2022
• Subjects: Animals; Calcitonin Gene-Related Peptide - metabolism; Endothelial Cells - metabolism; Humans; Hypoxia - metabolism; Lung - metabolism; lung function; Mice; neuropeptides; Neuropeptides - metabolism; pediatric disease; pulmonary neuroendocrine cells; pulmonary neuroendocrine cells; neuropeptides; pediatric disease; lung function
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.02.023

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions.
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•Increased PNECs are responsible for poor gas exchange in a NEHI mouse model•Increased PNECs and CGRP led to impaired endothelial barrier and excess fluid•Antagonizing CGRP signaling improved barrier and oxygenation in NEHI mouse mutants•Increased neuropeptides and reduced endothelial junctions were found in ARDS lungs
Xu et al. show that increased pulmonary neuroendocrine cells (PNECs), and secreted neuropeptides can cause poor gas exchange. In neuroendocrine hyperplasia of infancy (NEHI) mice, increased CGRP from PNECs causes vessel leakage, excess fluid, and poor oxygenation. These findings suggest neuropeptides as therapeutic targets for conditions with excess lung fluid.