Daily Ards Research Analysis

Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage-myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF.

OBJECTIVES: Mechanical power is a crucial concept in understanding ventilator-induced lung injury (VILI). We adopted the null hypothesis that under the same mechanical power, resulting from combinations of different static and dynamic variables-some with high stress per cycle and others without-would inflict similar degrees of damage on lung epithelial and endothelial cells as well as on the extracellular matrix in experimental acute respiratory distress syndrome (ARDS). To test this hypothesis, we varied tidal volume (V t ), which correlates with the stretching force per cycle, while adjusting respiratory rate (RR) to yield similar mechanical power values for identical durations across all experimental groups. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Thirty male Wistar rats (333 ± 26 g). INTERVENTIONS: Twenty-four hours after intratracheal administration of Escherichia coli lipopolysaccharide, animals were anesthetized and mechanically ventilated (positive end-expiratory pressure = 3 cm H 2 O) with combination of V t and RR sufficient to induce similar mechanical power ( n = 8/group): V t = 6 mL/kg, RR = 140 breaths/minute (low V t -high RR [LVT-HRR]); V t = 12 mL/kg, RR = 70 breaths/minute (high V t -low RR [HVT-LRR]); and V t = 18 mL/kg, RR = 50 breaths/minute (very-high V t -very-low RR [VHVT-VLRR]). All groups were ventilated for 80 minutes. A control group, not subjected to mechanical ventilation (MV), was used for molecular biology analyses. MEASUREMENTS AND MAIN RESULTS: After 80 minutes of MV, lung overdistension, alveolar/interstitial edema, fractional area of E-cadherin, and biomarkers of lung inflammation (interleukin-6), lung stretch (amphiregulin), damage to epithelial (surfactant protein B) and endothelial cells (vascular cell adhesion molecule 1 and angiopoietin-2), and extracellular matrix (versican and syndecan) were higher in group VHVT-VLRR than LVT-HRR. Plateau pressure and driving pressure increased progressively from LVT-HRR to HVT-LRR and VHVT-VLRR. CONCLUSIONS: In the current experimental model of ARDS, mechanical power alone is insufficient to account for VILI. Instead, the manner in which its components are applied determines the extent of injury at a given mechanical power value.

OBJECTIVE: Neutrophil elastase (NE) plays an important role in the development of acute respiratory distress syndrome (ARDS). Sivelestat sodium, as a selective NE inhibitor, may improve the outcomes of patients with sepsis-induced ARDS in previous studies, but there is a lack of solid evidence. This trial aimed to evaluate the effect of sivelestat sodium on oxygenation in patients with sepsis-induced ARDS. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial enrolling patients diagnosed with sepsis-induced ARDS admitted within 48 hours of the advent of symptoms. Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administered as a 24-hour continuous intravenous infusion, for a minimum duration of 5 days and a maximum duration of 14 days. The primary outcome was the proportion of PaO RESULTS: The study was stopped midway due to a potential between-group difference in mortality observed during the interim analysis. Overall, a total of 70 patients were randomized, of whom 34 were assigned to receive sivelestat sodium and 36 placebo. On day 5, 19/34 (55.9%) patients in the sivelestat group had PaO CONCLUSION: In patients with sepsis-induced ARDS, sivelestat sodium could improve oxygenation within the first five days and may be associated with decreased 28-day mortality.