The lung–brain axis and neuroinflammation: a convergence model and the role of exercise

Pulmonary and neurological disorders are increasingly recognized as interconnected manifestations of systemic neuroimmune dysregulation mediated by the lung–brain axis. Diverse pulmonary insults, including acute respiratory distress syndrome, chronic obstructive pulmonary disease, pneumonia, hypoxia, hypercapnia, and mechanical ventilation (MV), can contribute to central nervous system dysfunction. Although these triggers differ in origin, they may induce similar neuroimmune responses in the brain. In this Review, we propose a conceptual three-node convergence model. It integrates neurovascular and blood-brain barrier (BBB) dysfunction, peripheral-to-central immune activation with sustained microglial activation, and systemic redox imbalance with impaired mitochondrial resilience into a single pathological network. These processes do not act independently. Instead, they reinforce each other and form bidirectional crosstalk that spans multiple pulmonary conditions. Extracellular vesicle-mediated signalling and inflammasome activation act as key systemic amplifiers that drive and maintain this network across organs. Within this framework, exercise is repositioned as a systems-level regulator of neuroimmune function. It modulates neurovascular integrity, immunometabolic balance, and autonomic, neuroendocrine, and microbiota interactions in a coordinated manner. This integrative framework provides a conceptual basis for understanding lung–brain comorbidity as a systems-level disorder. It also supports the development of multi-target therapeutic strategies that go beyond single-pathway approaches. Pulmonary insults contribute to disrupted lung–brain homeostasis and the development of neurological dysfunction. The lung–brain axis operates as a three-node neuroimmune network integrating BBB disruption, immune–microglial activation, and mitochondrial-redox failure, which collectively drive neuroinflammation across pulmonary diseases, while exercise restores system homeostasis by simultaneously targeting all three nodes. Created with BioRender.com and Adobe illustrator.