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

Xu, Jinhao; Xu, Le; Sui, Pengfei; Chen, Jiyuan; Moya, Esteban A.; Hume, Patrick S.; Janssen, William J.; Duran, Jason; Thistlethwaite, Patricia A.; Carlin, Aaron F.; Gulleman, Peter M.; Banaschewski, B.; Goldy, M.K.; Yuan, Jason X.‐J.; Malhotra, Atul; Pryhuber, Gloria S.; Crotty-Alexander, Laura; Deutsch, Gail H.; Young, Lisa R.; Sun, Xin

doi:10.1016/j.devcel.2022.02.023

Cited by 23 publications

(13 citation statements)

References 54 publications

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“…In humans, PNECs are the cell type of origin for small cell lung cancer ( Ouadah et al, 2019 ). In a murine model of neuroendocrine hyperplasia of infancy (NEHI) with increased numbers of PNECs, elevated CGRP levels increase endothelial permeability leading to increased lung liquid and hypoxemia ( Xu et al, 2022 ). An increased number of PNECs has also been reported in a variety of lung diseases, although whether that is protective or detrimental remains uncertain ( Noguchi et al, 2020 ; Xu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In the lungs, pulmonary neuroendocrine cells (PNECs) are thought to be exclusively localized to surface epithelia where they are sparsely distributed or clustered at distal airway branch points ( Branchfield et al, 2016 ; Cho et al, 1989 ; Hogan et al, 2014 ; Kuo and Krasnow, 2015 ). They are chemosensory cells that respond to odorants, oxygen, mechanical stimuli, and allergens by releasing neurotransmitters and neuropeptides ( Cutz and Jackson, 1999 ; Gu et al, 2014 ; Lembrechts et al, 2012 ; Noguchi et al, 2020 ; Whitsett and Morrisey, 2016 ; Xu et al, 2020 ), which signal either parasympathetic afferents ( Chang et al, 2015 ; Liu et al, 2021 ; Su et al, 2022 ) or local immune and epithelial cells ( Branchfield et al, 2016 ; Sui et al, 2018 ; Xu et al, 2022 ). As examples, PNECs respond to allergens and hypoxia by stimulating mucus cell production and tissue repair by the airway surface epithelium ( Shivaraju et al, 2021 ; Sui et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction

Moninger

Rector

et al. 2022

Developmental Cell

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction

Moninger

Rector

et al. 2022

Developmental Cell

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“…CGRP was also found to activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. In this line, it was found to increase in human lung diseases with excess fluid, such as acute respiratory distress syndrome (ARDS)[ 55 ]. Based on these observations, since April 2020, the phase 2 clinical trial NCT04346615 is recruiting to evaluate the safety and efficacy trial of intranasal zavegepant intranasal for hospitalized patients with COVID-19 requiring supplemental oxygen began to investigate the use of intranasally administered zavegepant to combat the acute respiratory distress syndrome (ARDS) sometimes seen in patients with COVID-19.…”

Section: Clinical Trialsmentioning

confidence: 99%

Gepants — a long way to cure: a narrative review

et al. 2022

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Calcitonin gene-related peptide (CGRP) is probably the most potent vasodilator in cerebral circulation. Forty years after its discovery, the new CGRP-targeted therapy monoclonal antibodies, and the small molecule gepants, are now available for clinical practice. While randomized controlled trials and real-world experience consistently demonstrated the high efficacy and tolerability of monoclonal antibodies, limited evidence is available to characterize gepants fully. Depending on pharmacokinetics, these CGRP receptor antagonists can be used for acute (ubrogepant, rimegepant, and the not yet approved zavegepant) or preventive (atogepant and rimegepant) migraine treatment. Randomized placebo-controlled trials demonstrated gepants efficacy in treating acute attacks to obtain 2 h pain freedom in about 20% of patients and pain relief in about 60%, while up to 60% of treated patients with episodic migraine may experience a 50% reduction in monthly migraine days. The most common treatment-related emergent adverse events were gastrointestinal (nausea, constipation) for the acute or preventive use. No vascular or hepatic concerns have emerged so far. More studies are ongoing to investigate gepant tolerability and safety also if associated with monoclonal antibodies targeting CGRP and other therapeutic classes. Gepants are also under investigation to treat other painful and non-painful conditions. Real-life studies are necessary to confirm the trials’ findings and investigate more practical clinical aspects.

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“…Increased NEBs and even increased PNEC products have been recognized in several respiratory diseases previously, such as bronchopulmonary dysplasia, COPD, ARDS [ 66 ], and allergic asthma [ 67 ]. There was a rare study that discussed the involvement of Piezo2, expressed in NEBs, in these diseases.…”

Section: Piezo2 In the Respiratory Systemmentioning

confidence: 99%

Mechanosensitive Piezo channels mediate the physiological and pathophysiological changes in the respiratory system

et al. 2022

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Mechanosensitive Piezo ion channels were first reported in 2010 in a mouse neuroblastoma cell line, opening up a new field for studying the composition and function of eukaryotic mechanically activated channels. During the past decade, Piezo ion channels were identified in many species, such as bacteria, Drosophila, and mammals. In mammals, basic life activities, such as the sense of touch, proprioception, hearing, vascular development, and blood pressure regulation, depend on the activation of Piezo ion channels. Cumulative evidence suggests that Piezo ion channels play a major role in lung vascular development and function and diseases like pneumonia, pulmonary hypertension, apnea, and other lung-related diseases. In this review, we focused on studies that reported specific functions of Piezos in tissues and emphasized the physiological and pathological effects of their absence or functional mutations on the respiratory system.

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

Cited by 23 publications

References 54 publications

Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction

Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction

Gepants — a long way to cure: a narrative review

Mechanosensitive Piezo channels mediate the physiological and pathophysiological changes in the respiratory system

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