Daily Ards Research Analysis
Three studies advance ARDS/ALI science across mechanistic, translational, and therapeutic axes. A Redox Biology paper identifies MOTS-c as a nuclear-acting antioxidant regulator and perioperative biomarker predicting CPB-associated ARDS, while two preclinical studies show that rutin (via cGAS-STING-NLRP3 suppression) and vitamin E (via AMPK/NRF2/NF-κB and macrophage reprogramming) mitigate LPS-induced lung injury.
Summary
Three studies advance ARDS/ALI science across mechanistic, translational, and therapeutic axes. A Redox Biology paper identifies MOTS-c as a nuclear-acting antioxidant regulator and perioperative biomarker predicting CPB-associated ARDS, while two preclinical studies show that rutin (via cGAS-STING-NLRP3 suppression) and vitamin E (via AMPK/NRF2/NF-κB and macrophage reprogramming) mitigate LPS-induced lung injury.
Research Themes
- Mitochondrial-derived peptide MOTS-c as antioxidant transcriptional activator and ARDS biomarker after CPB
- Targeting cGAS-STING-NLRP3 axis to attenuate inflammatory lung injury
- Redox signaling and macrophage polarization as therapeutic levers in ALI/ARDS
Selected Articles
1. MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes.
In rat LIRI, MOTS-c translocates to the nucleus via MYH9 following ROS/CK2A-dependent MYH9 phosphorylation and directly engages ARE-containing promoters (e.g., HMOX1, NQO1) to activate antioxidant defenses. Clinically, perioperative ΔMOTS-c within 24 h post-CPB predicted ARDS (AUC 0.885), and exogenous MOTS-c reduced lung injury, inflammation, oxidative damage, and mortality in vivo.
Impact: This study links a mitochondrial peptide to nuclear antioxidant transcription, explains endothelial protection in LIRI, and introduces a perioperative biomarker with strong predictive performance for ARDS after CPB.
Clinical Implications: ΔMOTS-c could enable early risk stratification for CPB-associated ARDS and guide preventive strategies; MOTS-c analogs merit evaluation as prophylactic adjuncts to reduce LIRI-related complications.
Key Findings
- Endothelial cells showed prominent MOTS-c upregulation in rat LIRI with barrier preservation and reduced oxidative stress.
- ROS-CK2A-mediated phosphorylation of MYH9 (Ser1943) enabled MOTS-c binding to MYH9–γ-Actin complexes for nuclear transport.
- ChIP-seq and RNA-seq demonstrated MOTS-c occupancy at ARE-containing promoters (HMOX1, NQO1) and activation of antioxidant programs.
- Perioperative ΔMOTS-c within 24 h post-CPB predicted ARDS with AUC 0.885; multivariate models with ΔMOTS-c outperformed traditional biomarkers.
- Exogenous MOTS-c administration reduced lung injury, inflammation, oxidative damage, and mortality in vivo.
Methodological Strengths
- Integrated multi-omics (RNA-seq, ChIP-seq) with in vivo LIRI models and mechanistic signaling dissection
- Translational bridge with human perioperative biomarker analysis and predictive modeling
Limitations
- Human cohort size and external validation details are not reported, limiting generalizability
- No randomized clinical testing of MOTS-c therapy; species differences may affect translation
Future Directions: Prospective multicenter validation of ΔMOTS-c for ARDS prediction and phase I/II trials of MOTS-c or analogs for perioperative prophylaxis in high-risk CPB patients.
2. Rutin ameliorates LPS-induced acute lung injury in mice by inhibiting the cGAS-STING-NLRP3 signaling pathway.
In LPS-ALI mice, proteomics highlighted dysregulation of cytosolic DNA-sensing and NOD-like receptor pathways. Rutin reduced lung injury, oxidative stress, apoptosis, and proinflammatory cytokines, while dual-suppressing cGAS-STING (cGAS, STING, p-TBK1/p-IRF3) and NLRP3 pyroptosis (NLRP3–ASC–caspase-1–GSDMD). Pharmacologic STING blockade (C-176) confirmed pathway hierarchy.
Impact: Defines a dual-target anti-inflammatory mechanism for a widely available flavonoid in ALI, prioritizing the cGAS-STING–NLRP3 axis as a druggable pathway in ARDS/ALI.
Clinical Implications: Supports development of cGAS-STING/NLRP3-targeted strategies and positions rutin (or derivatives) as potential adjuncts for early ALI/ARDS management pending human studies.
Key Findings
- Proteomics showed activation of cGAS-STING and pyroptosis-related proteins in LPS-ALI lung tissue.
- Rutin reduced oxidative stress, apoptosis, and inflammatory cytokines (IL-6, IL-1β, TNF-α).
- Mechanistically, rutin inhibited cGAS, STING, and phosphorylation of TBK1/IRF3, and downregulated NLRP3–ASC–caspase-1–GSDMD signaling.
- STING inhibitor C-176 validated the cGAS-STING–NLRP3 regulatory hierarchy in ALI pathogenesis.
Methodological Strengths
- Comprehensive proteomics integrated with histology, molecular assays, and in vivo functional readouts
- Pharmacologic pathway validation using a selective STING inhibitor (C-176)
Limitations
- Single-species preclinical model without dose-response or pharmacokinetic bridging to humans
- Lack of long-term outcomes and external replication
Future Directions: Define dosing, PK/PD, and safety of rutin/analogs; test combinations with standard ARDS care; and evaluate cGAS-STING/NLRP3 signatures and response biomarkers in patients.
3. Vitamin E exerts a mitigating effect on LPS-induced acute lung injury by regulating macrophage polarization through the AMPK/NRF2/NF-κB pathway.
Vitamin E reduced injury indices and proinflammatory mediators in LPS-ALI, improved survival, and mitigated oxidative stress. Mechanistically, it activated AMPK, upregulated NRF2, inhibited NF-κB, scavenged ROS, and shifted macrophage polarization toward anti-inflammatory M2 while suppressing M1.
Impact: Identifies a redox-immune axis by which a clinically accessible antioxidant modulates macrophage polarization to blunt ALI, supporting repurposing strategies.
Clinical Implications: Supports testing vitamin E or analogs as adjunctive therapy in early ALI/ARDS and encourages macrophage-targeted strategies alongside standard care.
Key Findings
- Vitamin E decreased lung wet/dry ratio, reduced BALF proinflammatory cytokines, and improved survival in LPS-ALI mice.
- It alleviated oxidative stress by modulating redox products and scavenging ROS.
- Activated AMPK, upregulated NRF2, inhibited NF-κB signaling, and reprogrammed macrophage polarization toward M2 while suppressing M1.
Methodological Strengths
- Combined in vivo ALI model with in vitro BMDM mechanistic assays
- Demonstrated survival benefit alongside molecular pathway validation
Limitations
- Translational dosing and pharmacokinetics for humans are not defined
- Single animal model and strain; lack of long-term and multi-species validation
Future Directions: Determine optimal dosing and formulation, assess synergy with lung-protective ventilation and steroids, and conduct early-phase clinical studies in high-risk ALI/ARDS.