Metabolic response to injury and infection

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Chapter 86 Metabolic response to injury and infection

Ian K S. Tan

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

Following directed adhesion to endothelium and migration into tissue, neutrophils undergo an oxidative burst, producing a large variety of free radicals (species with one or more unpaired electrons) and reactive oxygen species (ROS), overwhelming natural scavenging and antioxidant defences, such as superoxide dismutase and glutathione peroxidase. These free radicals and ROS directly damage cells. Proteases, arachidonic acid metabolites (leukotrienes, thromboxanes and prostaglandins) and adhesion molecules are produced, amplifying the inflammatory cascade. Inducible nitric oxide synthase is activated, and nitric oxide is produced. Tissue macrophages become primed and activated.

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:

• TNF-α is a necessary and sufficient proximal mediator. After endotoxin challenge, TNF-α concentrations peak before other mediators. TNF-α administration reproduces all features of septic shock, including hypermetabolism, fever, anorexia, hyperglycaemia, decreased lipogenesis, marked protein catabolism and lactic acidosis. TNF-α activates the hypothalamic–pituitary–adrenal (HPA) axis. Soluble TNF-α receptors, a natural antagonist to TNF-α, also increase; this may be a regulatory response which contributes to later immunosuppression.
• IL-1β (endogenous pyrogen) produces much the same metabolic effects as TNF-α, and the combined effect of the two cytokines is greater than the effect of either alone. IL-1β is a potent inducer of the HPA axis as well as central and peripheral noradrenergic neurons. IL-6 is the main mediator of the acute phase response. Similar to TNF-α and IL-1β, IL-6 levels correlate with severity of illness and outcome. IL-8 induces neutrophil adhesion, chemotaxis and enzyme release. IL-2 generation is decreased. Anti-inflammatory cytokine (IL-4, IL-10, transforming growth factor-β) and antagonist (IL-1 receptor antagonist) levels increase. IL-4 activates B lymphocytes.
• Colony-stimulating factors stimulate the proliferation of haemopoietic cells, superoxide and cytokine production by neutrophils and macrophages. Disproportionate monocytopoiesis over granulocytopoiesis occurs. Erythropoietin production is suppressed.
• IFN-γ stimulates fibroproliferation, upregulates TNF receptors and induces TNF synthesis. IFN-γ production is synergistically induced by IL-12 and IL-18. IFN-α/β secretion is induced in viral infections and is proinflammatory.
• High mobility group box 1 (HMGB1) is a late proinflammatory mediator. It induces the expression of adhesion molecules in endothelial cells, increases enterocyte permeability, and further release of proinflammatory cytokines from leukocytes.
• Counter-inflammatory cytokines accumulate at the site of injury. Prostaglandin E2 inhibits further synthesis of inflammatory cytokines, and spermine inhibits their release. Transforming growth factor-β inhibits monocyte activation.

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:

• Reflex vagal efferent nerves secrete acetylcholine, which by binding to α7 subunits of the nicotinic receptor, suppresses proinflammatory cytokine synthesis from immunocytes.
• Reflex sympathetic efferents increase catecholamine levels, causing tachycardia and calorigenesis with increased oxygen consumption. Blood flow redistribution occurs depending on tissue receptor balance. Glycogenolysis, gluconeogenesis and lipolysis are stimulated. Activation of β2-adrenergic receptors decreases synthesis of proinflammatory cytokines and increases the synthesis of anti-inflammatory cytokines. However, α2-adrenoreceptor activation may increase TNF production.
• HPA axis activation results in high adrenocorticotropin hormone (ACTH) and cortisol levels, driving gluconeogenesis, proteolysis and lipolysis. Primarily by suppressing the nuclear factor (NF)-κB pathway, cortisol attenuates damage from excessive proinflammatory cytokine synthesis, while activating synthesis of anti-inflammatory IL-4 and IL-10. With prolonged critical illness, ACTH levels fall, but cortisol remains elevated with persistent loss of diurnal variation in secretion. Corticosteroid-binding globulin levels fall, and free cortisol levels may be increased. TNF decreases glucocorticoid response, and peripheral glucocorticoid resistance may vary between tissues.
• Growth hormone (GH) levels increase acutely with increased pulsatile frequency, but concomitant peripheral GH resistance occurs initially with low levels of GH-binding protein (GHBP) and insulin-like growth factor (IGF-1). Levels of the inversely regulated IGF-binding protein (IGFBP-1) increase, which correlates with mortality. Subsequently, loss of hypothalamic stimulation, as well as decreased ghrelin (a potent growth hormone secretagogue) levels, causes greatly reduced GH burst amplitudes, but peripheral GH sensitivity recovers.3
• The thyroid axis behaves in a similar fashion, with transient increases in thyrotropin (TSH) and thyroxine (T4) levels, and reduced conversion of T4 to tri-iodothyronine (T3). Chronically, reduced thyrotrophin-releasing hormone (TRH) secretion leads to low/normal levels and pulsatility in TSH, low T4 levels and further falls in T3 levels, termed the ‘sick euthyroid syndrome’.
• Prolactin (PRL) levels increase transiently, followed by reduced pulsatile amplitudes. As T-lymphocyte function is prolactin-dependent, this contributes to late loss of immune competence.
• Luteinising hormone (LH) levels increase transiently, followed by reduced pulsatile amplitudes. Low testosterone and high estradiol levels occur.4 Dehydroepiandrosterone levels are low. Estrogens inhibit proinflammatory cytokine production.
• α-Melanocyte stimulating hormone (α-MSH) levels increase, leading to immunosuppression via inhibition of the NF-κB pathway.
• Insulin and glucagon levels are increased but the insulin levels are inappropriately low for the level of hyperglycaemia. Insulin resistance is characterised by impaired glycogen synthesis. The increased glucagon:insulin ratio augments gluconeogenesis. Insulin has anti-inflammatory properties by inhibiting the NF-κB pathway, and prevents mitochondrial ultrastructural abnormalities, possibly by inhibiting hyperglycaemia-induced production of superoxide. Leptin levels increase acutely, then decrease.
• Procalcitonin levels increase and remain high, and its level correlates with severity of illness, so that procalcitonin has become a useful marker of systemic infection and a guide to therapy. Calcitonin levels, however, are variable and not necessarily elevated. Of the other members of the calcitonin superfamily, calcitonin gene-related peptide (CGRP) and adrenomedullin levels greatly increase; they are anti-inflammatory and contribute to vasodilatation.
• The renin–angiotensin–aldosterone axis is activated, causing fluid retention. Subsequently, aldosterone levels fall while renin remains elevated.
• Arginine vasopressin (AVP) levels increase initially, then return to normal or low levels despite persistent shock, in part due to depletion of stored hormone. Downregulation of V1 receptors (which mediate AVP’s vasoconstricting effect) occurs in sepsis.
• Vasoactive intestinal peptide secretion is induced, probably by nitric oxide, inhibiting production of proinflammatory cytokines and stimulating secretion of IL-10.

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.

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