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NEBS AND PIEZO2: GUARDIANS OF THE RESPIRATORY GALAXY

In a recent Nature publication, Schappe, M (2024) & team at Harvard Medical School uncover a fascinating role of sensory neurons in guarding against airway obstruction and orchestrating crucial reflexes to maintain respiratory function.

The study explores the intricate neural pathways involved in detecting and responding to airway closure. By characterizing a neuronal reflex of the vagus nerve evoked by airway closure, the researchers have identified dedicated sensory neurons that detect airway compression. They pinpointed the crucial role of neuroepithelial bodies (NEBs) and the mechanoreceptor PIEZO2 in sensing airway closure and initiating gasping responses.

Key Findings:

  • Identification of a vagal pathway sensing airway closure: The study uncovers a specialized pathway involving vagal sensory neurons and NEBs that detects and responds to airway closure, highlighting the complexity of respiratory reflexes.
  • Localization of gasp-promoting vagal terminals at NEBs: NEBs emerge as key players in airway mechanosensation, with their selective activation leading to gasping behavior.
  • Required role of NEBs in airway-closure-induced gasping: Knockout experiments reveal the indispensable contribution of NEBs in initiating gasping responses to airway closure.
  • Thoracic compression led to changes in lung mechanics, such as decreased lung compliance as measured by the flexiVent due to restricted chest wall movement.
  • vivoFlow plethysmography was used to investigate respiratory effects of activation of NEBs via chemogenetic approaches.
  • NEBABLATE mice did not gasp in response to airway closure, suction, or methacholine, unlike control mice. NEBABLATE mice also showed decreased compensatory changes in tidal volume during airway compression, indicating the importance of neuroepithelial bodies (NEBs) in maintaining normal lung mechanics.
  • Spontaneous sigh frequency was reduced in NEBABLATE mice, but the Hering–Breuer inspiratory reflex remained intact. Similarly, NEB-ΔPIEZO2 mice exhibited normal breathing but had decreased inspiratory capacity and lung compliance. These findings suggest that NEBs detect airway closure via PIEZO2 and signal to vagal PVALB neurons, ultimately evoking reflexive gasping behavior.
  • Cell atlas of NEB expression: Single-cell RNA sequencing provides insights into the molecular profile of NEBs, elucidating their role as mechanosensitive epithelial cells.
  • Importance of PIEZO2 in airway closure responses: Targeted knockout of PIEZO2 in NEBs abolishes airway-closure-induced gasps, underscoring its significance in respiratory reflexes.

The findings not only increase our understanding of airway mechanosensation but also offer potential insights into respiratory diseases characterized by airway obstruction. Moreover, they raise intriguing questions about the role of NEBs in human physiology and the sensation of air hunger.

Reference

Schappe, M.S., et al. (2024). A vagal reflex evoked by airway closure. Nature, doi.org/10.1038/s41586-024-07144-2

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