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.
Acute respiratory distress syndrome (ARDS) are major causes of mortality of critically ill patients. Impaired macrophage-mediated clearance of apoptotic cells (efferocytosis) in ARDS contributes to prolonged inflammation, yet the underlying mechanisms remain unclear. In this study, we investigated the role of geranylgeranyl diphosphate synthase (GGPPS) in efferocytosis during lung injury resolution. We identified dynamic changes in GGPPS expression in lung macrophages and circulating monocytes throughout the progression and resolution phases of acute lung injury (ALI). Myeloid-specific GGPPS knockout mice exhibited prolonged lung inflammation, increased accumulation of apoptotic neutrophils, a higher number of recruited macrophages, and a reduced number of resident macrophages. Notably, recruited macrophages play a dominant role in efferocytosis compared to resident macrophages. GGPPS deficiency suppressed efferocytosis in both macrophage subsets in vivo and in vitro. Mechanistically, GGPPS knockout disrupted AXL signaling in recruited macrophages. Importantly, administration of geranylgeraniol (GGOH) rescued the delayed resolution of lung injury, restored efferocytosis, and increased the suppressed AXL expression in CKO mice. Collectively, this study identifies GGPPS as a key regulator of AXL-mediated efferocytosis in recruited macrophages, highlighting its potential as a therapeutic target to accelerate ARDS resolution.
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.
RATIONALE: The significance of the Recruitment to Inflation (R/I) ratio in identifying PEEP recruiters in patients undergoing ultra-protective lung ventilation during venovenous ECMO is not well established. OBJECTIVES: To compare the concordance of the R/I ratio and Electrical Impedance Tomography (EIT) in determining optimum PEEP settings in severe ARDS patients on ECMO and ventilated with very low tidal volumes. METHODS: Initially, a low-flow insufflation was performed to detect and measure the airway opening pressure (AOP). Subsequently, the R/I ratio was calculated from PEEP 15-5 cmH MAIN RESULTS: Among 54 ECMO patients (tidal volume: 4.8 [3.0-6.0] mL/kg), 13 (24%) exhibited an airway opening pressure (AOP) of 11 (8-14) cmH CONCLUSION: The R/I ratio is feasible during ultra-protective ventilation and provides valuable indications for guiding PEEP titration. Specifically, an R/I ratio > 0.34 may help identify patients likely to benefit from further individualized PEEP optimization using EIT. In contrast, when the R/I ratio is ≤ 0.34, a moderate PEEP level (8-10 cmH₂O) may suffice.
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.
INTRODUCTION: The aim of this study is to evaluate clinical outcomes of critically-ill adult trauma patients with severe sepsis and severe injuries by body mass index (BMI) classification. METHODS: This retrospective study utilized the American College of Surgeons Trauma Quality Improvement Program database from 2017 to 2021 to evaluate the relationship between BMI and severe sepsis outcomes. Patients included in this study included critically-ill adult (age ≥18 ys) trauma patients with severe injuries (injury severity score [ISS] ≥15) and a diagnosis of severe sepsis. The primary outcome was in-hospital mortality. Secondary outcomes included intensive care unit length-of-stay, ventilation-free-days, and complications, including acute respiratory distress syndrome, deep vein thrombosis, pulmonary embolism, ventilator-associated pneumonia, and acute kidney injury. RESULTS: There were a total of 3268 patients included in this analysis. There was no significant association between obesity and odds of in-hospital mortality (odds ratio [OR]: 0.811, 95% confidence interval [CI]: 0.410-1.601, P = 0.545), intensive care unit length-of-stay (B = 5.114, 95% CI: -4.041-14.328, P = 0.268), ventilation-free-days (B = -0.280, 95% CI: -8.558-7.999, P = 0.946), deep vein thrombosis (OR: 1.625, 95% CI: 0.368-7.174, P = 0.522), pulmonary embolism (OR: 5.4 × 10ˆ14, 95% CI: 0.000-N/A, P = 0.992), acute respiratory distress syndrome (OR: 1.858, 95% CI: 0.668-5.179, P = 0.235), ventilator-associated pneumonia (OR: 0.809, 95% CI: 0.312-2.099, P = 0.664), or acute kidney injury (OR: 0.984, 95% CI: 0.449-2.154, P = 0.967) when compared to being normal weight. There was also no significant association between the remaining BMI classifications and all study outcomes. CONCLUSIONS: Obesity had no association with outcomes of severely injured critically ill adult trauma patients with severe sepsis as demonstrated through comparable clinical outcomes between study populations regardless of BMI classification.