• Mervyn Singer.
• Bloomsbury Institute of Intensive Care Medicine, Cruciform Building, University College London, London, WC1E 6BT, UK. m.singer@ucl.ac.uk.
• Crit Care. 2017 Dec 28; 21 (Suppl 3): 309.

AbstractAn exaggerated, dysregulated host response to insults such as infection (i.e. sepsis), trauma and ischaemia-reperfusion injury can result in multiple organ dysfunction and death. While the focus of research in this area has largely centred on inflammation and immunity, a crucial missing link is the precise identification of mechanisms at the organ level that cause this physiological-biochemical failure. Any hypothesis must reconcile this functional organ failure with minimal signs of cell death, availability of oxygen, and (often) minimal early local inflammatory cell infiltrate. These failed organs also retain the capacity to usually recover, even those that are poorly regenerative. A metabolic-bioenergetic shutdown, akin to hibernation or aestivation, is the most plausible explanation currently advanced. This shutdown appears driven by a perfect storm of compromised mitochondrial oxidative phosphorylation related to inhibition by excessive inflammatory mediators, direct oxidant stress, a tissue oxygen deficit in the unresuscitated phase, altered hormonal drive, and downregulation of genes encoding mitochondrial proteins. In addition, the efficiency of oxidative phosphorylation may be affected by a substrate shift towards fat metabolism and increased uncoupling. A lack of sufficient ATP provision to fuel normal metabolic processes will drive downregulation of metabolism, and thus cellular functionality. In turn, a decrease in metabolism will provide negative feedback to the mitochondrion, inducing a bioenergetic shutdown. Arguably, these processes may offer protection against a prolonged inflammatory hit by sparing the cell from initiation of death pathways, thereby explaining the lack of significant morphological change. A narrow line may exist between adaptation and maladaptation. This places a considerable challenge on any therapeutic modulation to provide benefit rather than harm.

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