Daily Ards Research Analysis
Three studies advance ARDS-related science across precision immunomodulation and host-directed antivirals. A multicenter target trial emulation shows corticosteroid effects in sepsis/pneumonia/ARDS vary by predicted organ dysfunction trajectory. Preclinical work identifies phillyrin as a GSK-3β–targeted modulator of sepsis-related ALI/ARDS and repurposes neurotransmitter receptor modulators to block influenza entry and improve survival in mice.
Summary
Three studies advance ARDS-related science across precision immunomodulation and host-directed antivirals. A multicenter target trial emulation shows corticosteroid effects in sepsis/pneumonia/ARDS vary by predicted organ dysfunction trajectory. Preclinical work identifies phillyrin as a GSK-3β–targeted modulator of sepsis-related ALI/ARDS and repurposes neurotransmitter receptor modulators to block influenza entry and improve survival in mice.
Research Themes
- Trajectory-based precision immunomodulation in sepsis/ARDS
- Host-directed antivirals targeting viral entry
- Macrophage polarization and GSK-3β signaling in ALI/ARDS
Selected Articles
1. Multicenter target trial emulation to evaluate corticosteroids for sepsis stratified by predicted organ dysfunction trajectory.
Using multicenter data and a two-stage ML approach, the authors subphenotyped and predicted organ dysfunction trajectories, then emulated a target trial of corticosteroids. The association between steroids and 28-day mortality differed by predicted trajectory across sepsis, pneumonia, and ARDS cohorts, supporting biology-driven treatment tailoring.
Impact: Introduces trajectory-based stratification to refine the evaluation of corticosteroids in sepsis/ARDS, moving beyond one-size-fits-all analyses. This framework can reshape trial design and bedside decision-making.
Clinical Implications: Avoid blanket steroid use; consider ML-predicted organ dysfunction trajectories to identify likely beneficiaries versus non-responders or potential harm. Prospective stratified RCTs are warranted before routine implementation.
Key Findings
- Two-stage ML defined and predicted organ dysfunction trajectories across sepsis, pneumonia, and ARDS.
- Target trial emulation showed steroid–mortality associations varied by predicted trajectory.
- Findings argue for matching immunomodulatory therapy to empirically observed pathobiology.
Methodological Strengths
- Retrospective multicenter design with target trial emulation
- Two-stage machine learning for subphenotyping and trajectory prediction
Limitations
- Observational design susceptible to residual confounding and indication bias
- Steroid dosing/timing and sample size details not specified in abstract
Future Directions: Prospective, trajectory-stratified randomized trials and integration of real-time trajectory prediction into clinical decision support.
2. Phillyrin for sepsis-related acute lung injury: A potential strategy suppressing GSK-3β.
Phillyrin targets GSK-3β to modulate innate immunity in sepsis-related ALI/ARDS. Multi-omics prioritization, docking/simulation, and validation in macrophages, zebrafish, and mouse ALI models show reduced NF-κB activation, lower TNF-α/IL-6, increased IL-10, M2 polarization, and attenuated lung injury.
Impact: Provides a mechanistically grounded, host-directed strategy for ALI/ARDS via GSK-3β inhibition using a natural product with in vivo efficacy.
Clinical Implications: While preclinical, the data support GSK-3β as a therapeutic target and phillyrin as a lead for drug development in sepsis-related ALI/ARDS.
Key Findings
- Identified six PHN-relevant hub genes; AKT1, GSK-3β, PPP2CA, PPP2CB, and PPP2R1A were overexpressed in ALI/ARDS datasets.
- Docking and dynamics simulations support a stable PHN–GSK-3β interaction.
- PHN reduced GSK-3β expression/activity, decreased NF-κB-p65 nuclear translocation, lowered TNF-α/IL-6, increased IL-10, promoted M2 polarization, and mitigated ALI/ARDS in zebrafish and mice.
Methodological Strengths
- Integrated multi-omics prioritization with molecular docking and dynamics
- Cross-validation in vitro (macrophages) and in vivo (zebrafish and mouse ALI models)
Limitations
- Preclinical study without human clinical data
- Reliance on in silico docking; pharmacokinetics, toxicity, and dosing not addressed
Future Directions: Define PK/toxicity and dose–response in mammals; test GSK-3β inhibition in clinically relevant sepsis/ARDS models; consider early-phase clinical trials.
3. Screening of neurotransmitter receptor modulators reveals novel inhibitors of influenza virus replication.
A host-directed screen identified neurotransmitter receptor modulators that inhibit influenza replication, with isoxsuprine reducing lung viral load, inflammation, and mortality in a lethal mouse model. These compounds act at early entry by impairing internalization and retain activity against oseltamivir-resistant strains.
Impact: Opens a host-targeting antiviral avenue that may circumvent resistance to neuraminidase/polymerase inhibitors and shows in vivo survival benefit.
Clinical Implications: Supports repurposing of approved/known neurotransmitter modulators (e.g., isoxsuprine, rotigotine) for severe influenza pending dose, safety, and efficacy trials; potential relevance to ARDS prevention via reduced viral burden and inflammation.
Key Findings
- Screening identified 20 neurotransmitter receptor modulators with IC50 < 20 μM against influenza.
- Isoxsuprine, ciproxifan, and rotigotine inhibited replication across multiple cell lines and strains, including oseltamivir-resistant H1N1, H3N2, and influenza B.
- Mechanism involves blocking early-stage internalization; isoxsuprine reduced lung viral titers, inflammation, and improved survival in lethal mouse influenza.
Methodological Strengths
- Host-directed library screen with validation across diverse strains and cell lines
- In vivo efficacy demonstrated with survival benefit in lethal mouse model
Limitations
- Toxicity, pharmacokinetics, and CNS/offs-target effects of neuromodulators not assessed
- Mechanistic depth limited beyond internalization; human data lacking
Future Directions: Define safety/PK and optimal dosing; test combination with standard antivirals; evaluate efficacy in severe pneumonia/ARDS models.