Kim Young Eun, Ahn So Yoon, Sung Se In, Yang Misun, Sung Dong Kyung, Park Won Soon, Chang Yun Sil
Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Republic of Korea.
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Republic of Korea.
Biomedicines. 2024 Mar 19;12(3):686. doi: 10.3390/biomedicines12030686.
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 HO-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.
从死亡或受损细胞中释放的线粒体DNA（mtDNA）可激活炎症反应，而间充质干细胞（MSC）移植可减轻炎症和损伤。然而，MSC移植是否能减少mtDNA的释放尚未得到验证。我们推测，在新生大鼠模型中，高氧诱导的肺损伤后细胞外mtDNA水平会升高，但MSC治疗减轻肺损伤后该水平会降低。在一项使用大鼠肺上皮L2细胞系的体外研究中，我们发现HO诱导细胞死亡后细胞外mtDNA水平显著升高，但与MSC共同孵育后降低。在一项体内研究中，我们证实高氧新生大鼠肺中的细胞死亡、细胞外mtDNA和炎性细胞因子水平显著升高，但MSC移植后降低。细胞外mtDNA水平与炎性细胞因子水平呈显著正相关。与mtDNA结合而激活的TLR9/MyD88/NF-κB通路在MSC移植后也显著上调但下调。我们发现插管新生儿的炎性细胞因子与细胞外mtDNA之间存在显著正相关。在插管新生儿的气管吸出物样本中，炎性细胞因子和细胞外mtDNA水平随时间以相似模式变化。总之，细胞外mtDNA水平升高与高氧诱导的肺损伤中炎症增加相关，而MSC治疗减轻肺部炎症与细胞外mtDNA水平降低相关。
