Dynamic reprogramming of alveolar epithelial-immune cell interactions in ARDS: from mechanisms to clinical translation

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome characterized by disruption of the alveolar-capillary barrier and refractory hypoxemia. Despite advances in supportive care, effective targeted therapies remain lacking. A major challenge to therapeutic success is the marked heterogeneity of ARDS, in which distinct biological mechanisms may drive different etiologies, inflammatory subphenotypes, and disease stages. Increasing evidence suggests that alveolar epithelial cells (AECs) are not merely passive targets of injury but active regulators of immune responses. Dynamic interactions between AECs and macrophages, neutrophils, and lymphocytes occur throughout the course of ARDS and contribute to inflammatory amplification, tissue repair, and aberrant remodeling. In this review, we summarize epithelial-immune interaction patterns across the inflammatory exudative, proliferative repair, and fibrotic phases of ARDS. We further discuss how disease stage transitions, immunometabolic regulation, and ARDS heterogeneity shape these interaction networks. Based on these findings, we present an AEC-centered dynamic reprogramming framework that organizes current evidence on how epithelial-immune interactions change during ARDS progression. We also discuss candidate biomarkers, approaches for clinical stage and phenotype identification, therapeutic opportunities, and current evidence limitations, aiming to provide a conceptual framework for stage-specific and precision interventions in ARDS. We further contextualize existing and controversial immunomodulatory strategies, including corticosteroids and IL-6/IL-1 blockade, within this dynamic framework to illustrate how disease stage and patient phenotype may influence therapeutic responses. Throughout the review, we distinguish evidence derived from experimental models from observational data in human ARDS and separately identify human interventional evidence and therapies supported by current clinical guidelines.