Immune Mechanisms and ECMO Strategies for Moderate-to-Severe ARDS

Acute respiratory distress syndrome (ARDS) poses a major threat to public health and consumes substantial healthcare resources. Based on the National Hospital Quality Monitoring System (HQMS), our group found that more than 2.5 million patients with ARDS are admitted to intensive care units (ICUs) annually in China, resulting in total hospitalization costs of approximately RMB 29.32 billion. The in-hospital mortality rate is about 39%, which is substantially higher than the international average (12-37%). Extracorporeal membrane oxygenation (ECMO) represents the most important rescue therapy for patients with moderate-to-severe ARDS; however, mortality among ARDS patients receiving ECMO support remains as high as 60%. Therefore, reducing mortality in moderate-to-severe ARDS is essential for achieving the goals of the Healthy China 2030 Initiative.

Inflammatory and immune dysregulation occurs in 38.7-70% of patients with ARDS, frequently leading to multiple organ dysfunction. Despite ECMO support, mortality among patients with severe ARDS remains extremely high. Three major challenges contribute to poor outcomes. First, immune dysregulation under ECMO support significantly increases the incidence and mortality of severe complications, while targeted therapeutic strategies based on underlying mechanisms are lacking. Second, the marked heterogeneity of ARDS complicates the identification of optimal timing and modalities of ECMO support. Third, the effects of different invasive mechanical ventilation strategies on lung injury and repair remain poorly understood, and mechanism-guided precision ventilation approaches are still unavailable.

Building upon the largest ARDS and ECMO clinical-biological database in China established by our group, this project aims to develop a Chinese precision management strategy for ECMO-supported patients with moderate-to-severe ARDS.

1. Comprehensive characterization of immune spatiotemporal dynamics in moderate-to-severe ARDS is essential for identifying therapeutic targets Current biomarkers reflecting disease progression in ARDS are largely limited to static clinical parameters and single-dimensional measurements, making biomarker-guided precision therapy difficult. Previous studies have identified biomarkers such as soluble receptor for advanced glycation end-products (sRAGE), angiopoietin-2 (Ang-2), and surfactant protein D (SPD) as prognostic indicators, yet these markers provide limited mechanistic insights and have not translated into individualized therapeutic strategies. Our group has established the largest ARDS and ECMO biospecimen cohort in China and has preliminarily characterized the spatiotemporal immune landscape of moderate-to-severe ARDS. We identified VCAM1 and tRF-5004b as potential immune-related targets closely associated with disease progression, providing a solid foundation for the proposed study.
2. Elucidating inflammatory and immune mechanisms underlying severe ECMO-related complications is critical for targeted intervention Among ARDS patients receiving ECMO support, the incidence rates of acute kidney injury (AKI), bleeding/thrombosis, and infection are approximately 45.7%, 40.2%, and 44.7%, respectively. Systemic inflammatory and immune dysregulation is considered a major contributor to these complications, although the underlying mechanisms remain unclear. In addition to the excessive inflammatory response characteristic of ARDS, restoration of oxygen delivery after ECMO initiation may trigger bursts of reactive oxygen species, calcium overload, and endothelial injury, thereby exacerbating inflammation and causing multiple organ dysfunction. Clarifying these mechanisms is essential for developing individualized interventions against severe ECMO-related complications.
3. Establishing multidimensional ARDS subphenotypes provides the basis for precision awake ECMO therapy ARDS is highly heterogeneous with respect to etiology, clinical manifestations, pathophysiology, and molecular characteristics, resulting in variable responses to ECMO support. Conventional classification based on oxygenation or isolated physiological parameters fails to capture the complex biological and immunological evolution of the disease. Our group previously identified hyperinflammatory and hypoinflammatory ARDS phenotypes using multidimensional clinical and biological data, but differences in ECMO responsiveness between these phenotypes have not been systematically investigated. Therefore, comprehensive characterization of ARDS biological heterogeneity and development of an integrated subphenotyping model incorporating clinical, physiological, imaging, and immune molecular features are required to identify patients most likely to benefit from awake ECMO.
4. Deciphering mechanisms of lung injury and repair is crucial for individualized mechanical ventilation strategies Inappropriate mechanical ventilation can exacerbate ventilator-induced lung injury and impair lung repair. Understanding the cellular and molecular mechanisms underlying lung injury and regeneration and clarifying the relationship between ventilatory parameters and tissue stress responses are fundamental to achieving personalized lung-protective ventilation. This project will integrate multimodal imaging, respiratory mechanics, and multi-omics data to characterize the dynamic processes governing lung injury and repair in ARDS, thereby establishing precision mechanical ventilation strategies to enhance lung protection and promote tissue recovery.

Perspectives and Expected Impact Focusing on the major challenges in the management of moderate-to-severe ARDS, this project will elucidate the mechanisms responsible for severe complications during ECMO support, establish a multidimensional phenotyping framework to identify patients most likely to benefit from awake ECMO, and decode the mechanisms of lung injury and repair to develop individualized ventilation strategies. Ultimately, this work will provide a comprehensive precision management framework for ECMO-supported ARDS patients, improve the standard of care for moderate-to-severe ARDS in China, and reduce disease-related mortality.