Abstract:

Objective

To investigate the protective effects and mechanisms of Maresin conjugates in tissue regeneration 3 (MCTR3) on the degradation of pulmonary vascular endothelial glycocalyx in mice with lipopolysaccharide (LPS)-induced acute respiratory distress syndrome(ARDS).

Methods

A total of 120 C57BL/6 mice were divided into four groups according to a random number table: a Control group， a LPS group， a LPS + MCTR3 group， and a MCTR3 group， with 30 mice in each group.The Control and MCTR3 groups received intratracheal administration of isotonic NaCl solution (50 μL)， while the LPS and LPS + MCTR3 groups intratracheally received LPS (1 mg/kg in 50 μL saline) to establish a ARDS model.Additionally，the LPS + MCTR3 and MCTR3 groups intravenously received MCTR3 (8 mg / kg).All groups were sampled 6 hours later.The clinical prognosis and related pathological changes were observed in each group.Electron microscopy was used to observe the structure of pulmonary vascular endothelial glycocalyx and alveolar epithelial cell mitochondria.

Results

After administering isotonic NaCl solution intratracheally for 4 days， there were no deaths in the Control and MCTR3 groups， whereas only one mouse survived in the LPS group， and four mice survived in the LPS + MCTR3 group.The difference in 4-d survival among the groups was statistically significant (χ²=22.810， P ＜0.001).Moreover， the 4-d survival of mice in the LPS group was significantly decreased compared with the Control and MCTR3 groups； the 4-d survival of mice in the LPS+MCTR3 group was significantly better than that of the LPS group (all P ＜0.001).The arterial partial pressure of oxygen (PaO₂)， oxygenation index， pathological injury scores， lung tissue wet/dry weight (W/D) ratio， tumor necrosis factor-alpha (TNF-α)， interleukin-1 beta (IL-1β)， endothelial glycocalyx degradation products of heparan sulfate proteoglycan 2(HSPG2) and syndecan-1 (SDC-1)， glycocalyx degradation marker heparanase (HPA)， endothelial glycocalyx-related protein SDC-1， mitochondrial-associated proteins of Sirtuin 1 (SIRT1)， peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)， nuclear respiratory factor 1(NRF1)， NRF2 and mitochondrial transcription factor A (TFAM)， and Flameng scores showed statistically significant differences among these four groups (F=8.812， 21.470， 123.451， 148.994，57.906， 92.948， 47.971， 88.109， 26.839， 31.928， 12.444， 5.537， 9.865， 12.423， 16.352， 294.910；all P ＜0.001).Further pairwise comparisons revealed that compared to the LPS group， the PaO₂，oxygenation index， and protein expression levels of SDC-1， SIRT1， PGC-1α， NRF1， NRF2 and TFAM were significantly higher， while the lung tissue pathological injury scores， W/D ratio， TNFα， IL-1β， HSPG2， SDC-1， HPA protein， and Flameng scores were reduced in the LPS + MCTR3 group (all P ＜0.05).

Conclusions

MCTR3 can improve clinical outcomes and pathological changes in ARDS mice， promoting the resolution of inflammation.Its potential mechanism may involve improving mitochondrial function in alveolar epithelial cells and reducing glycocalyx degradation in the pulmonary vasculature of ARDS mice.

Key words: Maresin conjugates in tissue regeneration 3, Acute respiratory distress syndrome, Endothelial glycocalyx, Mitochondrial function