Mesenchymal Stem Cells Reduce the Extracellular Mitochondrial DNA-Mediated TLR9 Activation in Neonatal Hyperoxia-Induced Lung Injury
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Published on: October 19, 2013
Young Eun Kim1,2, So Yoon Ahn1,3, Se In Sung3
1Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Republic of Korea.
Abstract:
Mitochondrial DNA (mtDNA) released from dead or injured cells can activate inflammation, and mesenchymal stem cell (MSC) transplantation can reduce inflammation and injury. However, it has not been tested whether the release of mtDNA can be reduced by MSC transplantation. We hypothesized that the level of extracellular mtDNA would be increased after hyperoxia-induced lung injury but reduced after lung injury attenuation by MSC therapy in our newborn rat model. In an in vitro study using a rat lung epithelial L2 cell line, we found that the level of extracellular mtDNA was significantly increased with H2O2-induced cell death but reduced after MSC co-incubation. In an in vivo study, we confirmed that the levels of cell death, extracellular mtDNA, and inflammatory cytokines were significantly increased in hyperoxic newborn rat lungs but reduced after MSC transplantation. The levels of extracellular mtDNA were significantly and positively correlated with the levels of the inflammatory cytokines. The TLR9/MyD88/NF-κB pathway, which is activated by binding to mtDNA, was also significantly upregulated but downregulated after MSC transplantation. We found a significant positive correlation between inflammatory cytokines and extracellular mtDNA in intubated neonates. The levels of inflammatory cytokines and extracellular mtDNA changed over time in a similar pattern in transtracheal aspirate samples from intubated neonates. In conclusion, increased levels of extracellular mtDNA are associated with increased inflammation in hyperoxia-induced lung injury, and attenuation of lung inflammation by MSC therapy is associated with reduced levels of extracellular mtDNA.
Insights
Mesenchymal stem cell (MSC) therapy reduced extracellular mitochondrial DNA (mtDNA) and inflammation in newborn rats with lung injury. This suggests MSCs can mitigate cell death and inflammatory responses linked to mtDNA release.
Area of Science:
- Biomedical Science
- Cell Biology
- Immunology
Background:
- Extracellular mitochondrial DNA (mtDNA) from damaged cells can trigger inflammation.
- Mesenchymal stem cell (MSC) transplantation is known to reduce inflammation and injury.
- The effect of MSC therapy on extracellular mtDNA levels in lung injury has not been previously investigated.
Purpose of the Study:
- To investigate whether MSC transplantation reduces extracellular mtDNA levels in a newborn rat model of hyperoxia-induced lung injury.
- To explore the correlation between extracellular mtDNA, inflammatory cytokines, and the TLR9/MyD88/NF-κB pathway in lung injury.
- To assess the clinical relevance of extracellular mtDNA and inflammation in intubated neonates.
Main Methods:
- In vitro studies using a rat lung epithelial cell line exposed to H2O2 to induce cell death.
- In vivo studies involving newborn rats exposed to hyperoxia to induce lung injury, followed by MSC transplantation.
- Analysis of extracellular mtDNA, inflammatory cytokines (e.g., IL-6, TNF-α), and the TLR9/MyD88/NF-κB pathway.
- Correlation analysis between measured parameters and assessment of transtracheal aspirate samples from intubated neonates.
Main Results:
- In vitro: H2O2-induced cell death increased extracellular mtDNA, which was reduced by MSC co-incubation.
- In vivo: Hyperoxia increased cell death, extracellular mtDNA, and inflammatory cytokines in newborn rat lungs; MSC transplantation reduced these markers.
- Extracellular mtDNA levels positively correlated with inflammatory cytokine levels and TLR9/MyD88/NF-κB pathway activation.
- A positive correlation between inflammatory cytokines and extracellular mtDNA was observed in intubated neonates, with similar temporal patterns in transtracheal aspirates.
Conclusions:
- Increased extracellular mitochondrial DNA is associated with heightened inflammation in hyperoxia-induced lung injury.
- Mesenchymal stem cell therapy effectively attenuates lung inflammation and reduces extracellular mtDNA levels.
- Extracellular mtDNA serves as a potential biomarker for inflammation in neonatal lung injury.
