Weekly Ards Research Analysis
This week’s ARDS literature highlights a mix of practice-changing clinical trial data and high-impact mechanistic/translational science. A large international RCT (PROTHOR) challenges routine intraoperative lung expansion during one-lung ventilation by showing no reduction in postoperative pulmonary complications and increased hemodynamic harms. Preclinical work nominates endothelial ALOX15 and its lipid mediators as protective in moderated pulmonary thrombosis, while mitochondrial transfer from
Summary
This week’s ARDS literature highlights a mix of practice-changing clinical trial data and high-impact mechanistic/translational science. A large international RCT (PROTHOR) challenges routine intraoperative lung expansion during one-lung ventilation by showing no reduction in postoperative pulmonary complications and increased hemodynamic harms. Preclinical work nominates endothelial ALOX15 and its lipid mediators as protective in moderated pulmonary thrombosis, while mitochondrial transfer from MSCs restores endothelial barrier function in ARDS models—together pointing to endothelial-targeted and cell-free therapies. Biomarker and multi-omics studies (including ML/ANN approaches and LLPS biology) continue to advance prognostic tools for phenotype-targeted trials.
Selected Articles
1. Unexpected Protective Role of Thrombosis in Lung Injury via Endothelial Alox15.
In murine sepsis-induced ALI/ARDS models, mild pulmonary thrombosis reduced endothelial apoptosis, lung injury severity, and mortality through sustained endothelial Alox15 expression. Severe thrombosis or thrombocytopenia worsened injury. Endothelial-targeted Alox15 overexpression and ALOX15-dependent lipid rescue mitigated lung injury, nominating ALOX15 and its lipid mediators as therapeutic targets.
Impact: This preclinical study overturns a common assumption by demonstrating that moderated thrombosis can be protective via endothelial ALOX15, providing an actionable lipid-enzyme pathway and strong mechanistic evidence (EC-targeted CRISPR/overexpression, lipidomics, in vivo rescue).
Clinical Implications: Cautions indiscriminate anticoagulation strategies in sepsis-related ARDS and supports exploration of ALOX15 upregulation or administration of protective ALOX15-dependent lipids, with priority for human validation and biomarker-driven stratification by thrombosis/platelet status.
Key Findings
- Mild pulmonary thrombosis reduced endothelial apoptosis, ALI severity, and mortality via sustained endothelial Alox15 expression.
- Severe pulmonary thrombosis or thrombocytopenia augmented sepsis-induced ALI.
- Endothelial Alox15 overexpression and ALOX15-dependent lipid rescue mitigated lung injury across models.
2. Effects of intraoperative higher versus lower positive end-expiratory pressure during one-lung ventilation for thoracic surgery on postoperative pulmonary complications (PROTHOR): a multicentre, international, randomised, controlled, phase 3 trial.
In a pragmatic international Phase 3 RCT of 2200 thoracic surgery patients undergoing one-lung ventilation, higher PEEP with recruitment maneuvers did not reduce postoperative pulmonary complications compared with lower PEEP without recruitment. High PEEP increased intraoperative hypotension and new arrhythmias. The trial provides high-level evidence to avoid routine lung-expansion strategies during one-lung ventilation in patients with BMI <35.
Impact: A large, pragmatic multicentre Phase 3 RCT that directly informs anesthetic ventilation protocols and perioperative practice by demonstrating lack of benefit and increased harm with routine high PEEP + recruitment during one-lung ventilation.
Clinical Implications: Avoid routine use of higher PEEP with recruitment during one-lung ventilation in patients with BMI <35; prefer individualized lower-PEEP/permissive-atelectasis strategies and close hemodynamic monitoring when higher PEEP is considered.
Key Findings
- No significant difference in postoperative pulmonary complications: high PEEP 53.6% vs low PEEP 56.4% (p=0.155).
- High PEEP markedly increased intraoperative hypotension (37.3% vs 14.3%) and new arrhythmias (9.9% vs 3.9%).
- Extrapulmonary postoperative complications and total adverse events were similar between groups.
3. Transplantation of mesenchymal stromal cell-derived mitochondria alleviates endothelial dysfunction in pre-clinical models of acute respiratory distress syndrome.
In translational preclinical studies, mitochondria isolated from human bone-marrow MSCs were internalized by pulmonary microvascular endothelial cells exposed to LPS or ARDS patient plasma, restoring mitochondrial function and endothelial barrier integrity without provoking inflammation. In LPS-challenged mice, intravenous MSC-derived mitochondria reduced lung injury, decreased alveolar inflammatory infiltration, and increased VE-cadherin mRNA, supporting development of cell-free mitochondrial therapies for ARDS.
Impact: Introduces cell-free mitochondrial transplantation as a mechanistically grounded therapeutic approach for endothelial dysfunction in ARDS, with primary human cell and in vivo validation—bridging bench to bedside potential for phenotype-targeted interventions.
Clinical Implications: Supports rapid development of cell-free mitochondrial/EV therapies for ARDS focused on endothelial repair; next steps include large-animal safety, biodistribution, dosing, and first-in-human feasibility studies with inflammatory-phenotype selection.
Key Findings
- MSC-derived mitochondria were internalized by HPMECs exposed to LPS or ARDS plasma and restored mitochondrial function and barrier integrity at 24 h.
- MSC-mt did not provoke cytotoxicity or pro-inflammatory responses in endothelial cells.
- In LPS-challenged mice, intravenous MSC-mt reduced lung injury, alveolar inflammatory infiltration, and increased lung VE-cadherin mRNA.