Abstract

Anxiety and depressive disorders are frequently comorbid with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Yet the mechanisms linking these conditions remain poorly understood. Previous studies have focused on the regulatory role of stress response on neuroendocrine pathways, while the role of immune regulatory networks in this process remains elusive. Here, we established a chronic restraint stress (CRS) mouse model to investigate how chronic psychological stress affects pulmonary function by regulating the immune system. CRS markedly impaired lung function and induced emphysema-like pathological changes. Mechanistically, CRS induced excessive recruitment and activation of alveolar macrophages, which in turn triggered a cascade of apoptosis-related signaling events. Specifically, alveolar macrophages exhibited upregulated Fas ligand (FASL) expression, which promoted the Fas death receptor signaling pathway and activated downstream effector caspases (Caspase-3, Caspase-6 and Caspase-7). The activation of this pathway ultimately triggered extensive apoptosis of lung parenchymal cells, resulting in significant tissue damage. Moreover, depletion of alveolar macrophages significantly attenuated apoptosis in pulmonary parenchymal cells and restored lung function. Collectively, our study identifies an important regulatory axis linking chronic psychological stress to macrophage recruitment and pulmonary dysfunction. These findings provide a novel mechanistic framework for understanding the comorbidity between psychological stress and respiratory diseases.