Summary of “Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies”
Abstract
This review addresses the growing complexity and heterogeneity of acute respiratory distress syndrome (ARDS), emphasizing its diverse pathophysiology, evolving clinical presentations, and variable treatment responses. Despite decades of study, ARDS remains a major cause of ICU mortality. The article explores the latest insights into the molecular mechanisms, including alveolar damage, immune dysregulation, and endothelial injury. It also highlights emerging therapeutic modalities such as immunotherapy, stem cell therapy, and precision-based interventions tailored to ARDS subtypes, including COVID-19-associated ARDS.
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70 years history of ARDS. Over the past 70 years, as research on ARDS has deepened, the definition of ARDS has gradually evolved, from “fluid overload” to the “Berlin definition”. This diagram shows important nodes in the evolution of ARDS definitions
Key Points:
ARDS Heterogeneity: ARDS is a syndrome with multiple etiologies, phenotypes, and immunopathologic mechanisms, making standardized treatment difficult and prompting a need for subtype-specific approaches.
Pathophysiologic Triad: Core mechanisms include alveolar epithelial damage, endothelial barrier disruption, and dysregulated immune responses—leading to impaired gas exchange and persistent lung injury.
Immune Dysregulation: Hyperinflammatory and hypo-inflammatory ARDS phenotypes have been identified, each exhibiting distinct biomarker profiles and differing therapeutic responses, which underpin the importance of patient stratification.
Endothelial Injury and Vascular Leakage: Endothelial dysfunction is a critical component, characterized by increased vascular permeability, leukocyte infiltration, and impaired repair—offering a target for vascular protective therapies.
Role of Neutrophils and NETs: Neutrophil extracellular traps (NETs) contribute significantly to lung tissue damage, suggesting a therapeutic opportunity in targeting neutrophil-mediated injury.
Mitochondrial Dysfunction and Cell Death: Bioenergetic failure, oxidative stress, and apoptotic or necroptotic pathways in alveolar cells further exacerbate lung injury and are active areas of translational research.
Emerging Therapies: Promising avenues include mesenchymal stem cell therapy, IL-6 inhibitors, JAK/STAT pathway blockers, and endothelial stabilizing agents, although many remain in early-phase trials.
Precision Medicine and Phenotyping: Tools such as transcriptomics, metabolomics, and machine learning are being applied to refine ARDS classification, enabling more personalized treatment strategies.
Future Directions: The integration of systems biology, bedside biomarkers, and real-time data analytics may revolutionize ARDS management, transforming it from a one-size-fits-all approach into a precision medicine model.
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The pathological changes in ARDS. Acute respiratory distress syndrome affects not only pulmonary tissue but also extra-pulmonary tissues. Systemic pathological changes, such as immunoinflammation and immunothrombosis, occur throughout the body, and various cells are involved in these pathological changes including macrophage, monocyte, dendritic cell, neutrophil, eosinophil, T cell and endothelial cell. These changes are believed to contribute to cellular abnormalities within the pulmonary tissue, ultimately leading to damage to the alveolar-capillary barrier in ARDS. A variety of pulmonary pathological changes have been observed in the damaged lung tissue, including endothelial barrier dysfunction, the presence of cell-free hemoglobin, reduced resolution of pulmonary edema, cell death, cellular senescence, and cellular dysfunction. *M1: Proinflammatory phenotype of macrophages; NET: neutrophil extracellular trap; CFH: cell-free hemoglobin; AFC: alveolar fluid clearance
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Cellular pathological changes in pulmonary tissue. In the pathological process of ARDS, neutrophils, macrophages, alveolar epithelial cells, endothelial cells, etc., interact with each other through various cytokines, leading to pathological changes including efferocytosis, NET formation, senescence, apoptosis, pyroptosis, ferroptosis, etc. *DAMPS damage-associated molecular patterns, MCP monocyte chemoattractant protein, MAPK mitogen-activated protein kinase, IL interleukin, METTL methyltransferase, GPX glutathione-peroxidase, NET neutrophil extracellular trap
Conclusion
ARDS remains a highly heterogeneous and deadly condition despite progress in supportive care. Understanding the molecular and immunological underpinnings of its subtypes has opened the door to personalized treatment strategies. Precision phenotyping, combined with targeted therapeutic innovations, represents the future direction in ARDS research and clinical management.
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Extracellular vesicle-based therapy in ARDS. EVs secreted by MSCs or other cells primarily exert their effects by cargos such as miRNAs and mitochondria. These contents can alleviate alveolar-capillary barrier damage, and regulate macrophage function, thereby achieving anti-inflammatory and immune regulatory functions. *EVs extracellular vesicles, MSC mesenchymal stromal cell, epi-EVs epithelium-derived extracellular vesicles, endo-EVs endothelium-derived extracellular vesicles
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Main therapies of ARDS. With the deepening of research, the treatment methods of ARDS have developed many new factions based on traditional treatment methods. Clinical trials have confirmed the effectiveness of cell therapy in the treatment of ARDS, especially stem cells and cell components. In addition, targeted therapy with targeted immunotherapy as its core also shows good therapeutic effects. However, due to the significant heterogeneity of ARDS, emerging evidence has revealed that personalized medicine should be administered in different ARDS subphenotypes. *Targeted therapy: Targeted therapy for ARDS focuses on interrupting or modifying specific molecular, genetic, or cellular mechanisms underlying lung injury and inflammation, thus reducing symptoms and improving outcomes. Personalized therapy: Personalized treatment of ARDS refers to developing personalized treatment methods based on the individual characteristics of the patient, such as genetic makeup, medical history, and unique disease manifestations, to optimize treatment efficacy and minimize side effects. HFNO high-flow nasal cannula oxygen, NIV noninvasive ventilation, PEEP positive end-expiratory pressure, ARDS Acute respiratory distress syndrome, CARDS COVID-19 related acute respiratory distress syndrome, TNF-α tumor necrosis factor alpha, GM-CSF granulocyte-macrophage colony-stimulating factor, KGF keratinocyte Growth Factor, NET neutrophil extracellular trap, TNFSF14 lymphocyte-inducing protein, NLRP3 NOD-, LRR- and pyrin domain-containing 3, NF-κB nuclear factor kappa B, STAT signal transducer and activator of transcription, Nrf2: nuclear factor-E2-related factor 2
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