Acute Respiratory Distress Syndrome: Pathophysiological Insights, Subphenotypes, and Clinical Implications—A Comprehensive Review

Increased epithelial and endothelial permeability, along with dysregulated inflammatory responses, are key aspects of acute respiratory distress syndrome (ARDS) pathophysiology, which not only impact the lungs but also contribute to detrimental organ crosstalk with distant organs, ultimately leading to multiple organ dysfunction syndrome (MODS)-the primary cause of morbidity and mortality in patients with lung injury (LI) and ARDS. It is predominantly manifested by hypoxemic respiratory failure and bilateral pulmonary infiltrates, which cannot be fully attributed to cardiac failure or hypervolemia, but rather to alveolo-capillary barrier dysfunction, dysregulated systemic and pulmonary inflammation, immune system abnormalities, and mechanical stimuli-related responses. However, these pathological features are not uniform among patients with ARDS, as distinct subphenotypes with unique biological, clinical, physiological, and radiographic characteristics have been increasingly recognized in recent decades. The severity of ARDS, clinical outcomes, mortality, and efficacy of applied therapeutic measures appear significant depending on the respective phenotype. Acknowledging the heterogeneity of ARDS and defining distinct subphenotypes could significantly modify therapeutic strategies, enabling more precise and targeted treatments. To address these issues, a comprehensive literature search was conducted in PubMed using predefined keywords related to ARDS pathophysiology, subphenotypes, and personalized therapeutic approaches. Optimizing the identification and characterization of discrete ARDS subphenotypes-based on clinical, biological, physiological, and radiographic criteria-will deepen our understanding of ARDS pathophysiology, promote targeted recruitment in prospective clinical studies to define patient clusters with heterogeneous therapeutic responses, and support the shift toward individualized treatment strategies.