Division of Surgery and Interventional Science, University College London, Royal Free Hospital, London, NW3 2QG, UK; Intensive Care Unit, Royal Free Hospital, London, NW3 2QG, UK; Peninsula Medical School, University of Plymouth, John Bull Building, Derriford, Plymouth, PL6 8BU, UK.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.
Redox Biol. 2021 May;41:101907. doi: 10.1016/j.redox.2021.101907. Epub 2021 Feb 20.
Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support.
To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients.
We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors' FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups.
Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.
多种病理学导致多器官衰竭，据认为这是细胞生物能量状态受损的直接后果。这种表型的性质及其与生存的相关性尚不清楚，这限制了现代生命支持的疗效。
为了探讨从危重病中存活与细胞生物能量变化相关的假设，我们结合了对线粒体呼吸的评估以及骨骼肌和血液中的代谢组学、脂质组学和氧化还原谱分析，在 21 名危重病患者和 12 名参考患者中，在多个时间点进行。
我们在危重病中证明了一种终末器官细胞表型，其特征是总能量能力保持不变，与健康相比，耦合效率更高，而 I 型复合物和脂肪酸氧化（FAO）支持的呼吸能力选择性降低。在幸存者中，48 小时时的 I 型复合物能力比非幸存者低 27%（p=0.01），但在第 7 天有上升趋势，而非幸存者则没有这种恢复。到第 7 天，幸存者的 FAO 酶活性是非幸存者的两倍（p=0.048），而非幸存者的血浆三酰甘油积累。与健康相比，在早期危重病中观察到细胞氧化应激和还原驱动力的明显增加。最初，非幸存者的血浆总抗氧化能力较高，但最终比幸存者的脂质过氧化水平更高。这些变化与非幸存者中循环总游离巯基和亚硝酰化物种的水平更高相对应，表明非幸存者的还原应激和血管炎症比幸存者更大。相比之下，两组之间未观察到系统炎症标志物的明显差异。
危重病与细胞呼吸机制、中间代谢和氧化还原反应的快速、特定和协调改变有关，幸存者和非幸存者的轨迹不同。揭示人类适应能力的细胞和分子基础可能会使开发更有效的生命支持策略成为可能。
