Latvian Institute of Organic Synthesis, Riga, LV, Latvia.
Faculty of Biology, University of Latvia, Riga, LV, Latvia.
Shock. 2019 Dec;52(6):e153-e162. doi: 10.1097/SHK.0000000000001315.
Significant impairments in mitochondrial function are associated with the development of multi-organ failure in sepsis/endotoxaemia, but the data on the dynamics of simultaneous mitochondrial impairment in multiple organs are limited. The aim of this study was to evaluate the changes in heart, brain and kidney mitochondrial function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia.Samples were collected 4 and 24 h after single injection of LPS (10 mg/kg) in mice. Marked increases in inflammation-related gene expression were observed in all studied tissues 4 h after LPS administration. At 24 h post LPS administration, this expression of inflammation-related genes remained upregulated only in kidneys. Significantly increased concentrations of kidney function markers confirmed that kidneys were severely damaged. Echocardiographic measurements showed that the ejection fraction and fractional shortening were significantly reduced 4 h after LPS administration, whereas 24 h after LPS administration, the cardiac function was restored to baseline. A two-fold decrease in mitochondrial oxidative phosphorylation (OXPHOS) capacity in the kidney was observed 4 and 24 h after LPS administration. Significant decrease in mitochondrial fatty acid oxidation was observed in heart 4 h after LPS administration. Furthermore, 24 h after LPS administration, the respiration rates in cardiac fibers at OXPHOS and electron transport (ET) states were significantly increased, which resulted in increased ET coupling efficiency in the LPS-treated group, whereas four-fold increases in the H2O2 production rate and H2O2/O ratio were observed. The brain mitochondria demonstrated a slightly impaired mitochondrial functionality just 24 h after the induction of endotoxaemia.In conclusion, among studied tissues kidney mitochondria are the most sensitive to endotoxaemia and do not recover from LPS-induced damage, whereas in brain, mitochondrial function was not significantly altered. In heart, endotoxaemia induces a decrease in the mitochondrial fatty acid oxidation capacity, but during the phase of suppressed inflammatory response, the ET efficiency is improved despite the marked increase in reactive oxygen species production.
线粒体功能的严重损伤与脓毒症/内毒素血症多器官衰竭的发展有关，但关于多个器官同时发生线粒体损伤的动态数据有限。本研究旨在评估脂多糖（LPS）诱导内毒素血症的实验模型中心、脑和肾线粒体功能的变化。在 LPS（10mg/kg）单次注射后 4 和 24 小时收集样本。LPS 给药后 4 小时，所有研究组织中炎症相关基因表达均明显增加。LPS 给药后 24 小时，仅肾脏中炎症相关基因的表达仍上调。肾脏功能标志物浓度的显著增加证实肾脏严重受损。超声心动图测量显示，LPS 给药后 4 小时，射血分数和缩短分数明显降低，而 LPS 给药后 24 小时，心脏功能恢复至基线。LPS 给药后 4 和 24 小时，肾脏的线粒体氧化磷酸化（OXPHOS）能力降低了两倍。LPS 给药后 4 小时，心脏中线粒体脂肪酸氧化显著减少。此外，LPS 给药后 24 小时，OXPHOS 和电子传递（ET）状态下心肌纤维的呼吸率显著增加，导致 LPS 处理组 ET 偶联效率增加，而 H2O2 产生率和 H2O2/O 比值增加了四倍。大脑线粒体仅在诱导内毒素血症 24 小时后表现出线粒体功能轻度受损。总之，在所研究的组织中，肾脏线粒体对内毒素血症最敏感，并且不能从 LPS 诱导的损伤中恢复，而在大脑中，线粒体功能没有明显改变。在心脏中，内毒素血症会降低线粒体脂肪酸氧化能力，但在炎症反应受抑制的阶段，尽管活性氧产生显著增加，但 ET 效率得到改善。
