Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis

BACKGROUND

The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging.

AIM

To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EX^AD) and exogenous mitochondria (mito^Ex) protect the lung from ARDS complicated by SS.

METHODS

In vitro study, including L2 cells treated with lipopolysaccharide (LPS) and in vivo study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EX^AD), 4 (ARDS-SS + mito^Ex), and 5 (ARDS-SS + EX^AD + mito^Ex), were included in the present study.

RESULTS

In vitro study showed an abundance of mito^Ex found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (P < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EX^AD treatment than without EX^AD treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all P < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11^b/c+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all P < 0.0001), whereas arterial oxygen-saturation (SaO₂%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO₂% among the groups (all P < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all P < 0.0001).

CONCLUSION

Combined EX^AD-mito^Ex therapy was better than merely one for protecting the lung against ARDS-SS induced injury.

Key Words: Acute respiratory distress syndrome, Sepsis syndrome, Exosomes, Mitochondria, Adipose tissue-derived mesenchymal stem cells, Inflammation

Core Tip: To investigate whether combined adipose-derived mesenchymal-stem-cells-derived exosome (EX^AD) and exogenous mitochondria (mito^Ex) protect the lung from acute respiratory distress syndrome complicated by sepsis syndrome. The results of this study showed that combined EX^AD and mito^Ex exerted a synergic effect on protecting the lung from acute respiratory distress syndrome complicated by sepsis syndrome mainly by suppressing inflammatory reaction and oxidative stress, resulting in improved respiratory system and outcomes.

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• Citation: Lin KC, Fang WF, Yeh JN, Chiang JY, Chiang HJ, Shao PL, Sung PH, Yip HK. Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis. World J Stem Cells 2024; 16(6): 690-707
• URL: https://www.wjgnet.com/1948-0210/full/v16/i6/690.htm
• DOI: https://dx.doi.org/10.4252/wjsc.v16.i6.690

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