Daily Ards Research Analysis
Three studies advance ARDS science across pathophysiology and therapeutics: autopsy-based evidence distinguishes in situ pulmonary thrombosis from embolic PE in COVID-19 ARDS; a first-in-class GPR68 inhibitor restores endothelial barrier function and reduces LPS-induced lung injury; and a cyclodextrin-complexed inhalable plasminogen retains fibrinolytic activity under oxygen-rich nebulization and lyses clots in vitro.
Summary
Three studies advance ARDS science across pathophysiology and therapeutics: autopsy-based evidence distinguishes in situ pulmonary thrombosis from embolic PE in COVID-19 ARDS; a first-in-class GPR68 inhibitor restores endothelial barrier function and reduces LPS-induced lung injury; and a cyclodextrin-complexed inhalable plasminogen retains fibrinolytic activity under oxygen-rich nebulization and lyses clots in vitro.
Research Themes
- Distinct thrombotic phenotypes in ARDS (in situ thrombosis vs pulmonary embolism)
- Endothelial barrier protection via GPCR signaling (GPR68) in lung injury
- Targeted fibrinolysis: inhalable plasminogen formulations for ARDS
Selected Articles
1. In situ pulmonary thrombosis and pulmonary embolus are distinct thrombotic phenotypes in critically ill patients with COVID-19 Acute Respiratory Distress Syndrome.
Autopsy-based classification in 21 COVID-19 ARDS decedents showed that in situ thrombosis originates from the pulmonary vessel wall and differs histologically, radiologically, and immunologically from embolic PE. IST was associated with higher IL-17, IL-18, and IL-33 levels and wall-adherent irregular filling defects on CT, supporting distinct immune-driven thrombosis.
Impact: It reframes pulmonary thrombosis in ARDS by separating IST from PE with multimodal evidence, informing diagnostic imaging and anticoagulation strategies.
Clinical Implications: Recognition of IST may influence anticoagulation intensity, thrombolysis considerations, and targeted anti-inflammatory approaches; CT patterns (wall-adherent defects in small arteries) and cytokine profiles could aid differentiation from PE.
Key Findings
- Histology distinguished IST (vessel wall-origin, disorganized thrombus) from PE (central, layered thrombus).
- CT in IST showed irregular wall-adherent filling defects in smaller arteries within areas of infiltrates.
- IST cases had higher IL-17, IL-18, and IL-33 compared to PE and non-thrombosis controls.
- Cohort composition: IST n=6, PE n=8, controls n=7 among 21 COVID-19 ARDS decedents.
Methodological Strengths
- Multimodal assessment integrating histopathology, serology, and radiology.
- A priori phenotypic criteria for IST vs PE with blinded pathology evaluation.
Limitations
- Small, single-disease autopsy cohort (COVID-19), limiting generalizability to non-COVID ARDS.
- Observational design without interventional testing; potential selection bias in decedents.
Future Directions: Prospective imaging-biomarker studies to validate IST signatures in vivo and trials testing tailored anticoagulation or immunomodulation for IST.
2. Novel small molecule inhibitor of GPR68 attenuates endothelial dysfunction and lung injury caused by bacterial lipopolysaccharide.
The first-in-class GPR68 inhibitor OGM-8345 suppressed LPS-induced endothelial gap formation, adherens junction disassembly, hyperpermeability, NF-κB activation, and expression of ICAM-1/VCAM-1, with protective effects across macro- and microvascular lung ECs and in post-treatment settings. In vivo, OGM-8345 reduced vascular leak and inflammation in LPS-exposed mouse lungs.
Impact: Identifies GPR68 as a mechanistic driver of endothelial barrier failure in inflammatory lung injury and proposes a tractable drug target with demonstrated in vivo efficacy.
Clinical Implications: Supports development of GPR68 inhibitors as endothelial-stabilizing therapeutics for ARDS and sepsis-related lung injury, potentially complementing ventilation and anti-inflammatory care.
Key Findings
- OGM-8345 inhibited LPS-induced GPR68 activity and prevented endothelial paracellular gap formation and adherens junction disassembly.
- Suppressed NF-κB activation and reduced ICAM-1/VCAM-1 expression and cytokine/chemokine transcription in lung ECs.
- Protection observed across macrovascular and microvascular lung ECs and in post-treatment models using LPS or CRX-527.
- In vivo, OGM-8345 reduced Evans blue extravasation, BAL total protein and cells, and inflammatory gene expression in mouse lungs.
Methodological Strengths
- Mechanistic convergence across in vitro endothelial models and in vivo lung injury.
- Selectivity supported by lack of effect with a GPR4 inhibitor and use of post-treatment paradigms.
Limitations
- Preclinical LPS models may not capture full complexity of human ARDS.
- No human pharmacokinetic/safety data; potential off-target effects remain uncharacterized.
Future Directions: Evaluate GPR68 inhibition in diverse ARDS models (infectious and sterile) and initiate translational safety/pharmacology studies toward early-phase clinical trials.
3. Plasminogen-cyclodextrin aerosol for ARDS: activity retention in simulated oxygen therapy and inflammation-triggered clot lysis.
Complexing plasminogen with HP-β-cyclodextrin protected oxidation-prone residues, preserved >95% enzymatic activity post-nebulization under oxygen flow, and achieved lung-depositable aerosol characteristics (MMAD ~2.1 μm, FPF ~84%). The formulation lysed human clots in both urokinase-triggered and cell-activated models, supporting translational potential for ARDS fibrin burden.
Impact: Demonstrates a practical hospital-ready inhalable fibrinolytic that withstands oxygen-rich delivery, addressing a key barrier to local fibrinolysis in ARDS.
Clinical Implications: Supports development of inhaled plasminogen therapy to target alveolar fibrin in ARDS, potentially improving oxygenation while limiting systemic bleeding risk compared with systemic thrombolysis.
Key Findings
- HP-β-CD complexation shielded oxidation-sensitive methionines, confirmed by spectroscopy and FT-IR; in silico modeling showed HP-β-CD binding near methionine residues.
- Post-nebulization enzymatic activity under oxygen flow remained >95% with HP-β-CD vs ~57% for unprotected plasminogen.
- Aerosol metrics favored lung deposition: MMAD ~2.1 μm and FPF ~84% via mesh nebulization.
- Human clot lysis was achieved in both urokinase-triggered and LPS-macrophage–activated models; D-dimer confirmed fibrinolysis.
Methodological Strengths
- Convergent validation using spectroscopy, FT-IR, and computational docking for mechanistic protection.
- Integrated aerodynamic characterization with functional enzymatic and cell-activated clot lysis assays.
Limitations
- No in vivo ARDS or safety data; translational efficacy in the injured lung remains untested.
- Repurposed eye-drop formulation requires regulatory pathway and device–drug compatibility validation.
Future Directions: Evaluate safety, lung distribution, and efficacy in ARDS animal models under oxygen therapy and initiate early clinical feasibility studies.