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

Acute respiratory distress syndrome (ARDS) poses a major threat to human health. Despite extracorporeal membrane oxygenation (ECMO) support, mortality among patients with ARDS remains high due to severe complications and suboptimal mechanical ventilation strategies. Elucidating the mechanisms underlying ECMO-related complications and lung injury repair, and establishing a precision intervention pathway covering the entire course of ECMO management, are urgent unmet needs for improving outcomes in ARDS patients and addressing major public health challenges.

This project focuses on five key scientific questions:

1. How can moderate-to-severe ARDS be classified into distinct clinical-immune phenotypes, and what are the optimal therapeutic targets for each phenotype? 2. What are the molecular mechanisms underlying severe complications in ARDS patients receiving ECMO support? 3. Which key immune biomarkers are associated with clinical benefit from awake ECMO? 4. How should mechanical ventilation strategies be optimized in moderate-to-severe ARDS patients supported with ECMO? 5. How can a comprehensive, full-cycle ECMO management pathway be established for patients with moderate-to-severe ARDS?

The project consists of five interrelated subprojects:

Subproject 1. Construction of Clinical-Immune Phenotypes and Identification of Therapeutic Targets in Moderate-to-Severe ARDS Clinical phenotypes and longitudinal multidimensional biospecimens collected throughout the disease course in moderate-to-severe ARDS patients, including those receiving ECMO support, will be analyzed to characterize the heterogeneity and spatiotemporal interactions of inflammatory and immune cell subsets and to identify effective therapeutic targets.

Subproject 2. Mechanisms and Interventions for Immune Dysregulation Underlying Severe ECMO-Related Complications This subproject aims to elucidate the inflammatory and immune mechanisms responsible for major complications occurring in ARDS patients receiving ECMO support. Major complications of interest include acute kidney injury, bleeding and thrombosis, and infection.

Subproject 3. Development and Validation of a Clinical-Immune Phenotype-Guided Decision System for Awake ECMO By integrating multidimensional data, a comprehensive ARDS phenotyping framework will be established to identify patients most likely to benefit from awake ECMO. A clinical decision-making system will be developed and subsequently validated through multicenter studies to assess its effectiveness.

Subproject 4. Molecular Mechanisms of Lung Repair and Optimization of Mechanical Ventilation During ECMO Support This subproject will investigate the lung-protective effects of different invasive mechanical ventilation strategies and ventilation parameters during ECMO support. Multi-omics analyses of ARDS biospecimens will be performed to elucidate the mechanisms through which lung rest promotes tissue repair and recovery.

Subproject 5. Establishment and Evaluation of a Full-Cycle ECMO Management Strategy for Moderate-to-Severe ARDS Based on evidence-based medicine and multidisciplinary collaboration, a comprehensive ECMO management pathway covering the entire disease course will be developed for patients with moderate-to-severe ARDS. Real-world studies will be conducted to evaluate its clinical effectiveness and facilitate continuous optimization.

Overall, this project aims to provide mechanistic insights into immune dysregulation, ECMO-related complications, and lung repair, while establishing a precision, full-cycle ECMO management framework to improve outcomes in patients with moderate-to-severe ARDS.\*\*