Chapter 86 Metabolic response to injury and infection
Injury and infection evoke in the host a hypermetabolic inflammatory response and a compensatory hypometabolic hypoimmune response. The magnitude of the response is proportional to the extent of injury. Additional components of illness, such as ischaemia and reperfusion or resuscitation, nutritional status, surgical procedures, transfusions, drugs and anaesthetic techniques, genetic polymorphisms and concurrent diseases, impact on the response. Some components of the metabolic response, or the failure to regulate the response, are destructive, and its modulation may improve patient survival.1
MEDIATORS OF THE METABOLIC RESPONSE
CYTOKINES
NEUROENDOCRINE MEDIATORS
Cytokine release from the site of injury or infection triggers vagal afferent impulses to the dorsal vagal complex (DVC) in the medulla oblongata. Synaptic connections with the rostroventral medulla and locus ceruleus, and the hypothalamic nuclei, activate the sympathetic nervous system and the HPA axis respectively.2 High circulating cytokine levels may also cross the blood–brain barrier, or affect neurons at circumventricular organs lacking a blood–brain barrier, such as the area postrema. In general, a biphasic response is observed following injury and infection: an initial neuroendocrine ‘storm’ followed by a decrease. The following are some neuroendocrine mediators involved in the response to stress:
THE METABOLIC RESPONSE
The metabolic response to injury and infection begins with the activation of receptors throughout the body by the above mediators. These receptors include toll-like receptors (TLR)-2 and TLR-4, and the receptor for advanced glycation end products (RAGE). Subsequent intracellular activation of the NF-κB pathway leads to gene induction and production of mRNA for the synthesis of proinflammatory cytokines. Catecholamines can initiate rapid functional changes via protein phosphorylation, which does not require gene induction. Behavioural effects such as anorexia, possibly due to elevated leptin levels, also affect the metabolic response. The metabolic effects may be described at three levels.
CELLULAR METABOLIC EVENTS
Intracellularly, heat shock protein (HSP) synthesis is induced. Many HSPs are also expressed constitutively. HSPs act as ‘chaperones’, assisting in the assembly, disassembly, stabilisation and internal transport of other intracellular proteins. HSPs facilitate translocation of the glucocorticoid-receptor complex from the cytosol to the nucleus, and inhibit NF-κB activity. HSPs have cellular protective roles in sepsis and ischaemia-reperfusion.5
Mitochondrial dysfunction limits cell metabolism and may be responsible for the ensuing multiorgan dysfunction of severe injury and infection. Electron transport chain complexes are inhibited by excessive nitric oxide and peroxynitrite generated during sepsis.6 Additionally, poly (ADP-ribose) polymerase-1 (PARP-1) is activated, reducing cell nicotinamide adenine dinucleotide (NADH) content, a substrate for ATP generation. The reduced ATP production may have functional consequences, such as diaphragmatic dysfunction.7 It has been hypothesised that this ‘metabolic shutdown’ is an adaptive response similar to hibernation.8
Apoptosis, or programmed cell death, may finally be induced when death receptors are engaged by their ligands, or by mitochondrial-mediated pathways.9 Death receptors include Fas and TNF receptor type I (TNFRI), and this pathway activates caspase. The mitochondrial pathway, mediated in part by glycogen synthase kinase-3β activation, causes activation of caspase. Caspases 8 and 9 activate caspase 3, which commits the cell to death. TNF-α, IL-10, cortisol and nitric oxide all induce apoptosis. Apoptosis further augments immunosuppression. It is probable that bioenergetic failure and the apoptotic death of immune cells are the major causes of death in late sepsis.
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