Daily Ards Research Analysis

Acute respiratory distress syndrome and pulmonary fibrosis stemming from severe acute lung injury (ALI) continue to incur high mortality due to ineffective pulmonary regeneration. While metabolic reprogramming is known to support alveolar epithelial repair, the specific role of amino acid metabolism remains enigmatic. Through integration of scRNA-seq mining analysis of human ALI samples and targeted plasma metabolomics, we identified that lysine was largely declined in injured pulmonary epithelium, accompanied by a deficiency of mitochondrial metabolism. Lysine supplementation dramatically improved survival (from 0% to 62.5% in mice), attenuated extracellular matrix deposition and alveolitis, and suppressed inflammation in murine and non-human primate ALI models. Mechanistically, lysine replenished acetyl-CoA to restore α-tubulin acetylation for rescuing ciliary TRPC1 localization, which prevented pathological STIM1-TRPC1 complex formation, thereby blocking calcium influx-reduced E-Cadherin/ZO-1 abundance in pulmonary epithelial cells. Notably, ciliogenesis preferentially occurred in SFTPC+ alveolar epithelial type II (AT2) cells; thus, lysine supplementation would promote regenerative activation of AT2 cells. Our work established lysine as a metabolic-structural orchestrator that coordinates acetyl-CoA availability to calcium homeostasis and epithelial repair through tubulin-mediated ciliary signaling.

Mechanical ventilation contributes to lung injury in acute respiratory distress syndrome, yet whether cumulative mechanical energy, the time-integrated delivery of ventilatory power, adequately reflects the risk of ventilator-induced lung injury (VILI) remains uncertain. Because lung tissue exhibits nonlinear stress-strain behaviour, the rate and amplitude of energy delivered may be as relevant as its magnitude. We tested whether different combinations of tidal volume (VT) and ventilation duration, matched for cumulative energy, produce distinct patterns of VILI following endotoxin-induced lung damage in male Wistar rats. Animals received intratracheal lipopolysaccharide and, after 24 h, were mechanically ventilated (PEEP=3 cmH₂O; inspired oxygen fraction=0.40) using one of three strategies: VT=6 mL/kg for 150 min (LVT-HMV), VT=9 mL/kg for 100 min (MVT-MMV), or VT=12 mL/kg for 75 min (HVT-LMV). Apparatus dead space was adjusted to maintain normocapnia. An LPS-exposed, non-ventilated group served as molecular and histological reference. Despite equivalent cumulative energy exposure, HVT-LMV resulted in higher plateau and driving pressures, greater alveolar overdistension, collapse, and pulmonary edema, and increased expression of interleukin-6 and vascular cell adhesion molecule-1. MVT-MMV produced intermediate structural injury with selective upregulation of mechanosensitive extracellular matrix markers, whereas LVT-HMV was associated with the least injury. Driving and plateau pressures correlated with indices of overdistension and extracellular matrix signaling but showed weaker associations with endothelial activation. These findings indicate that VILI depends not only on total energy delivery but also on its temporal distribution, and that cumulative energy alone is insufficient to predict lung injury risk.

BACKGROUND: Granulocyte and monocyte adsorption therapy has been explored as an adjunctive treatment for sepsis due to its potential to modulate excessive systemic inflammation. However, clinical evidence characterizing its real-world use for sepsis remains limited. This study aimed to conduct an exploratory comparative assessment of granulocyte and monocyte adsorption apheresis-direct hemoperfusion (G1-DHP) in patients with sepsis. METHODS: We conducted a retrospective comparative study using a prospective multicenter dataset of patients treated with G1-DHP (G-1 trial) and three independent sepsis datasets (Japan Septic Disseminated Intravascular Coagulation [JSEPTIC-DIC], Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma [FORECAST], and Japan Medical Data Center [JMDC]) as controls. Propensity score matching was performed using one-to-one nearest-neighbor matching. The primary outcome was 28-day mortality. Secondary outcomes included ventilator-free period, intensive care unit (ICU)-free period, and improvements in organ dysfunction scores. Ordinal logistic regression and linear regression were used based on outcome characteristics. RESULTS: After matching, the cohorts included 71, 72, and 68 patient pairs for comparisons with JSEPTIC-DIC, FORECAST, and JMDC, respectively. 28-day mortality was significantly lower in the G-1 trial across all matched datasets (G-1 trial vs. JSEPTIC-DIC: 5.6% vs. 23%; G-1 trial vs. FORECAST: 5.6% vs. 28%; G-1 trial vs. JMDC: 5.9% vs. 38%, all P < 0.01). The G-1 trial had a significantly longer ventilator-free period and a trend toward a longer ICU-free period. G1-DHP was also associated with greater observed improvement in Sequential Organ Failure Assessment (SOFA) score by day 7 in comparison to controls. Improvements in liver and coagulation SOFA subscores were particularly notable. CONCLUSIONS: In this multi-dataset analysis, patients treated with G1-DHP showed lower mortality and more favorable clinical outcomes in comparison to external controls. These exploratory findings provide preliminary insights into the potential role of G1-DHP as an immunomodulatory approach in sepsis and warrant further evaluation in prospective studies.