Lung-Innervating Neurons in Lung Homeostasis and Diseases

The lung, classically viewed as a gas exchange organ, is increasingly recognized as a dynamic sensory interface that continuously monitors the external environment and communicates with the brain to shape physiology and disease. Vagal sensory neurons provide the predominant afferent innervation of the airways, displaying striking molecular diversity, distinct projection patterns, and specialized terminal morphologies that enable detection of mechanical, chemical, and immune-derived signals. These neurons orchestrate critical homeostatic functions, including breathing regulation, airway protection, and cardiopulmonary integration, while also contributing to pathological processes such as airway hyperreactivity, inflammation, and neuroimmune remodeling. Recent advances in molecular profiling, genetic tools, and circuit-mapping approaches have revealed new principles of vagal sensory organization, yet fundamental questions remain about how specific neuronal subtypes encode diverse environmental inputs, how their signals are integrated within central circuits, and how disease reshapes these pathways. This review synthesizes current knowledge of lung-innervating vagal sensory neurons, emphasizing their roles in neuroimmune cross talk, central integration, and disease pathogenesis. We highlight unresolved controversies and propose future directions aimed at decoding the molecular logic of airway sensation, mapping neuroimmune signaling, and developing organ-specific neuromodulation strategies to treat lung diseases. Together, these insights position vagal sensory pathways as central players in the lung-brain axis and promising therapeutic targets at the intersection of respiratory, immune, and neural health.