Neuropsychiatric disorders in pulmonary fibrosis: from brain network alterations to inflammatory mechanisms and therapeutic implications

Pulmonary fibrosis encompasses a spectrum of chronic lung diseases characterized by progressive scarring of lung tissue, ultimately leading to respiratory failure. Emerging clinical evidence indicates that pulmonary fibrosis patients frequently experience comorbid neuropsychiatric disorders, including cognitive impairment, anxiety, and depression. These complications significantly impact patients' quality of life and treatment outcomes. However, the mechanisms underlying this comorbidity remain incompletely understood, and there is a lack of effective interventions. This review summarizes the latest clinical evidence linking pulmonary fibrosis to neuropsychiatric complications and contributes to the understanding of the underlying mechanisms through the lung-brain axis theory. Studies indicate that various pulmonary fibrosis subtypes, including idiopathic pulmonary fibrosis and pneumoconiosis, exhibit high prevalence of neuropsychiatric disorders and abnormal brain networks, indicating a close pathophysiological connection between pulmonary fibrosis and neuropsychiatric complications. At the mechanistic level, accumulating experimental evidence suggests that pulmonary fibrosis may induce central nervous system damage through three interrelated pathways: (1) Systemic dissemination of pulmonary inflammation leads to blood-brain barrier disruption and microglial activation; (2) Chronic hypoxia exacerbates neuroinflammation and synaptic dysfunction; (3) The inhaled particulate matter enters the brain from the olfactory mucosa through the olfactory bulb or crosses the damaged alveolar capillary barrier, enters the circulation, and then passes through the already damaged blood-brain barrier, inducing local neurotoxicity. Furthermore, we advocate for actively exploring a comprehensive treatment model that shifts from "lung-focused therapy" to "lung-brain co-therapy". This approach employs multiple interventions-including medication, pulmonary rehabilitation training, and cognitive training-to prevent or delay systemic complications, including neuropsychiatric damage, in pulmonary fibrosis patients. Elucidating the lung-brain axis in pulmonary fibrosis may open new avenues for a more comprehensive understanding, early intervention, and holistic management of this devastating disease.