Early-life lung injury and the developing brain: a lung-brain axis perspective on neurodevelopmental disorders

Emerging evidence indicates that early-life lung injuries-including bronchopulmonary dysplasia, childhood asthma, recurrent respiratory infections, and environmental tobacco smoke exposure-are significantly associated with an increased risk of neurodevelopmental disorders such as cognitive impairment, autism spectrum disorder, attention-deficit/hyperactivity disorder, and emotional or behavioral affections. The developing brain is particularly vulnerable during infancy and childhood, and pulmonary insults during this critical window may disrupt normal neurodevelopment through multiple interconnected mechanisms along the lung-brain axis. These mechanisms include the hypoxia-oxidative stress axis, which impairs oligodendrocyte maturation and myelination; pulmonary microvascular injury leading to neuronal energy metabolism dysregulation; systemic inflammation-mediated disruption of the blood-brain barrier; and a cascade from pulmonary inflammation to neuroinflammation, characterized by microglial activation, synaptic dysfunction, and impaired myelination. Together, these pathways converge to produce long-lasting neurodevelopmental consequences. Understanding the lung-brain axis provides a novel theoretical framework for explaining this comorbidity and highlights the need to integrate neurodevelopmental risk assessment and early intervention into the clinical management of early-life lung diseases. Future research should focus on longitudinal cohorts, identification of critical developmental windows, and targeted therapeutic strategies that address both pulmonary and neurological health.