The Role of the Nervous System in Lung Disease

Peripheral nerves regulate pulmonary physiology in a nerve-type- and compartment-specific manner through neurotransmitters, neurotrophins and axon-guidance cues. This review examines how sensory and autonomic pathways influence pulmonary homeostasis and disease, and evaluates the experimental models available to investigate these interactions.

Dysregulated pulmonary innervation has been implicated in acute lung injury, airway hyperresponsiveness, pulmonary fibrosis and lung cancer, where neural signals may modulate immune activation, stromal remodelling and tumour progression. However, pulmonary neurobiology remains comparatively underexplored, in part because neuronal cell bodies are located outside the lung and pulmonary axons and nerve terminals are sparse, fragile and difficult to resolve using conventional methods. Rodent models remain essential for establishing causal mechanisms within intact neural circuits, although species-specific differences limit direct translation. Human pluripotent stem cell-derived sensory and autonomic neurons offer a platform for dissecting human nerve-immune and nerve-stromal interactions. Integration of mechanistic animal studies with human stem cell-derived neuronal models may overcome current experimental limitations and provide a more physiologically relevant framework for defining the contribution of pulmonary nerves to respiratory disease.