CYTOKINES

Cytokines are soluble, non-antibody, regulatory proteins released from the activated immunocytes, and are responsible primarily for the inflammatory and counter-inflammatory response. Injury and infection cause cytokine release from activated leukocytes, endothelial cells and fibroblasts. T-helper type 1 (TH1) lymphocytes primarily impact cell-mediated immunity and secrete tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2) and interferon-γ (IFN-γ), while TH2 lymphocytes impact antibody-mediated immunity and secrete IL-4 and IL-10. The TH1/TH2 cytokine profile determines the immunostimulatory/immunosuppressive balance. Cytokines generally exert their effects in a paracrine fashion, but in severe injury and infection, they enter the circulation and act as hormones. The following are major cytokines involved in the response to stress:

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:

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.