Daily Ards Research Analysis
A mechanistic study identifies the GGPPS–AXL axis as a key regulator of macrophage efferocytosis and resolution of acute lung injury, suggesting a new therapeutic target for ARDS. A physiologic cohort of VV-ECMO patients shows that a bedside R/I ratio threshold (0.34) can triage who may benefit from EIT-guided PEEP optimization. A national retrospective cohort finds no association between BMI and mortality or complications (including ARDS) in severely injured trauma patients with severe sepsis.
Summary
A mechanistic study identifies the GGPPS–AXL axis as a key regulator of macrophage efferocytosis and resolution of acute lung injury, suggesting a new therapeutic target for ARDS. A physiologic cohort of VV-ECMO patients shows that a bedside R/I ratio threshold (0.34) can triage who may benefit from EIT-guided PEEP optimization. A national retrospective cohort finds no association between BMI and mortality or complications (including ARDS) in severely injured trauma patients with severe sepsis.
Research Themes
- Macrophage efferocytosis mechanisms in ARDS resolution (GGPPS–AXL axis)
- Individualized PEEP titration on VV-ECMO using R/I ratio and EIT
- Impact of BMI on outcomes in severely injured trauma patients with severe sepsis
Selected Articles
1. Geranylgeranyl diphosphate synthase deficiency impairs efferocytosis and resolution of acute lung injury.
Using myeloid-specific GGPPS knockout models, the study shows that loss of GGPPS impairs AXL-dependent efferocytosis in recruited macrophages, prolonging lung inflammation and delaying resolution of acute lung injury. Geranylgeraniol restored efferocytosis and AXL expression, positioning the isoprenoid pathway as a modifiable target to accelerate ARDS resolution.
Impact: This work uncovers a previously unrecognized GGPPS–AXL mechanism controlling macrophage efferocytosis, providing a concrete, druggable pathway for enhancing lung injury resolution.
Clinical Implications: While preclinical, targeting the isoprenoid pathway (e.g., augmenting GGPPS activity or AXL signaling) could enhance efferocytosis and hasten resolution in ARDS. Translational studies in human ARDS macrophages and early-phase trials of pathway modulators are warranted.
Key Findings
- GGPPS expression dynamically changes in lung macrophages and circulating monocytes across ALI progression and resolution.
- Myeloid-specific GGPPS knockout prolongs lung inflammation, increases apoptotic neutrophil accumulation, raises recruited macrophages, and reduces resident macrophages.
- Recruited macrophages dominate efferocytosis; GGPPS deficiency suppresses efferocytosis in both recruited and resident subsets in vivo and in vitro.
- GGPPS knockout disrupts AXL signaling in recruited macrophages, and geranylgeraniol restores efferocytosis and AXL expression, rescuing delayed resolution.
Methodological Strengths
- Myeloid-specific conditional knockout with in vivo ALI models and in vitro validation
- Mechanistic linkage to AXL signaling with pharmacologic rescue by geranylgeraniol
Limitations
- Preclinical animal study; human validation and clinical translatability remain to be established
- Dosing, safety, and efficacy of pathway modulation (e.g., GGOH) in humans are unknown
Future Directions: Validate the GGPPS–AXL axis in human ARDS macrophages, define recruited vs resident macrophage targeting strategies, and test small-molecule or gene-based modulators in translational models and early-phase trials.
2. Optimum electrical impedance tomography-based PEEP and recruitment-to-inflation ratio in patients with severe ARDS on venovenous ECMO.
In 54 VV-ECMO severe ARDS patients ventilated with very low tidal volumes, bedside R/I measurement was feasible and informative for PEEP titration. An R/I ratio >0.34 flagged patients likely to benefit from individualized EIT-based PEEP optimization, whereas R/I ≤0.34 supported moderate PEEP (8–10 cmH2O).
Impact: Provides an actionable physiological threshold (R/I 0.34) to triage VV-ECMO patients for advanced EIT-guided PEEP titration during ultra-protective ventilation.
Clinical Implications: R/I ratio can be measured at the bedside to guide PEEP: if >0.34, consider individualized EIT-guided optimization; if ≤0.34, moderate PEEP (8–10 cmH2O) may suffice, potentially avoiding overdistension during ECMO.
Key Findings
- In 54 VV-ECMO patients with severe ARDS (tidal volume 4.8 [3.0–6.0] mL/kg), 24% had a measurable airway opening pressure with median 11 (8–14) cmH2O.
- Bedside R/I ratio assessment from PEEP 15–5 cmH2O was feasible during ultra-protective ventilation.
- R/I >0.34 identified patients likely to benefit from further individualized PEEP optimization using EIT; R/I ≤0.34 suggested that moderate PEEP (8–10 cmH2O) may be adequate.
Methodological Strengths
- Prospective physiologic assessment including low-flow insufflation to measure airway opening pressure
- Use of EIT to inform optimal PEEP during ultra-protective ventilation on VV-ECMO
Limitations
- Observational physiologic study without randomized comparison or patient-centered outcome endpoints
- Single-session assessment; modest sample size and technology availability (EIT) may limit generalizability
Future Directions: Validate the 0.34 threshold in multicenter cohorts and test protocolized R/I-guided vs EIT-guided PEEP strategies for effects on oxygenation, ventilator-induced lung injury, and clinical outcomes.
3. Association of Body Mass Index With Severe Sepsis Outcomes in Critically-Ill Severely Injured Adult Trauma Patients: A National Analysis.
In 3,268 severely injured adult trauma patients with severe sepsis, BMI categories were not associated with in-hospital mortality, ICU length of stay, ventilator-free days, or complications including ARDS, DVT, PE, VAP, and AKI. Findings argue against an obesity paradox in this specific population.
Impact: A large, national dataset shows no BMI-outcome association, providing a robust negative result that refines risk stratification and counters assumptions of an obesity paradox in severely injured, septic trauma patients.
Clinical Implications: BMI alone should not influence prognostication or management strategies for severely injured trauma patients with severe sepsis; resource allocation and prevention strategies (e.g., VTE prophylaxis) should be similar across BMI categories.
Key Findings
- N=3,268 severely injured adult trauma patients (ISS ≥15) with severe sepsis from 2017–2021 ACS TQIP.
- Obesity showed no association with in-hospital mortality (OR 0.811, 95% CI 0.410–1.601, P=0.545).
- No association between obesity and ICU length of stay, ventilator-free days, or complications including ARDS, DVT, PE, VAP, and AKI.
- No BMI category had significant associations with any study outcomes.
Methodological Strengths
- Large national database (ACS TQIP) with 3,268 patients and multiple clinically relevant outcomes
- Use of multivariable analyses to estimate adjusted associations
Limitations
- Retrospective observational design with potential residual confounding and coding bias
- Sparse data for rare events (e.g., pulmonary embolism) produced unstable estimates
Future Directions: Prospective studies testing targeted care pathways irrespective of BMI and exploring body composition or metabolic phenotypes beyond BMI in septic trauma populations.