I

Oxidants Antioxidant \ He defence <( pr

defence

Feedback systems

Heat-shock proteins Glucose

T- and B-cells

Pathogen killing

Tissue damage

Nutrient release from host tissues

Glutamine

Sulphur amino acids

Acute-phase protein synthesis

—► Glutathione synthesis

Antioxidant defences i /

strengthened

Fig. 7.5. The response of the immune system to infection and injury and the effects upon metabolism.

the response to microbial invasion, by a wide range of stimuli and conditions; these include burns, penetrating and blunt injury, the presence of tumour cells, environmental pollutants, radiation, exposure to allergens and the presence of chronic inflammatory diseases. The strength of the response to this disparate range of stimuli will vary, but it will contain many of the hallmarks of the response to invading pathogens. The immune response has a high metabolic cost, and inappropriate prolongation of the response will exert a deleterious effect upon the nutritional status of the host.

The pro-inflammatory cytokines interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-a have widespread metabolic effects upon the body and stimulate the process of inflammation. Many of the signs and symptoms experienced after infection and injury, such as fever, loss of appetite, weight loss, negative nitrogen, sulphur and mineral balance and lethargy are caused directly or indirectly by pro-inflammatory cytokines (Fig. 7.5). The indirect effects of cytokines are mediated by actions upon the adrenal glands and endocrine pancreas, resulting in increased secretion of the catabolic hormones adrenalin, noradren-alin, glucocorticoids and glucagon. Insulin insensitivity occurs, in addition to this 'catabolic state'. The biochemistry of an infected individual is thus fundamentally changed in a way that will ensure that the immune system receives nutrients from within the body. Muscle protein is catabolized to provide amino acids for synthesizing new cells, GSH and proteins for the immune response.

Furthermore, amino acids are converted to glucose (a preferred fuel, together with glutamine, for the immune system). An increase in urinary nitrogen and sulphur excretion occurs as a result of this catabolic process. The extent of this process is highlighted by the significant increase in urinary nitrogen excretion, from 9 g day-1 in mild infection to 20-30 g day-1 following major burn or severe traumatic injury (Wilmore, 1983). The loss of nitrogen from the body of an adult during a bacterial infection may be equivalent to 60 g of tissue protein and, in a period of persistent malarial infection, equivalent to over 500 g of protein. However, during the response to infection and injury, the urinary excretion of sulphur increases to a lesser extent than that of nitrogen (Cuthbertson, 1931), suggesting that sulphur amino acids are preferentially retained and so 'spared' from catabolism. Infection with human immunodeficiency virus (HIV) has been shown to cause substantial excretion of sulphate in the urine during the asymptomatic phase of the disease (Breitkreutz et al., 2000). The losses reported were equivalent to 10 g of cysteine day-1, in contrast to losses of approximately 3 g day-1 for healthy individuals on a 'Westernized diet'. As cysteine is the precursor for both sulphate and GSH this finding may be linked with the decline in tissue glutathione pools that has been observed in HIV infection (De Rosa et al., 2000). Clearly, such a depletion of antioxidant defences will not be sustainable over a long period.

Large decreases in plasma glycine, serine and taurine concentrations occur following infection and injury. These changes may be due to enhanced utilization of a closely related group of amino acids, namely, glycine, serine, methion-ine and cysteine. Many substances produced in enhanced amounts in response to pro-inflammatory cytokines are particularly rich in these amino acids. These substances include GSH, which comprises glycine, glutamic acid and cysteine, metallothionein (the major zinc-transport protein), which contains glycine, serine, cysteine and methionine to a composite percentage of 56%, and a range of acute-phase proteins, which contain up to 25% of these amino acids in their structure. If an increased demand for sulphur and related amino acids is created by the inflammatory response, then provision of additional supplies of these amino acids may assist the response.

Many of the components of antioxidant defence interact to maintain antioxidant status (see also Hughes, Chapter 9, Prasad, Chapter 10, and McKenzie et al., Chapter 12, this volume). Glutathione and the enzymes that maintain it in its reduced form are central to effective antioxidant status. For example, when oxidants interact with cell membranes, the oxidized form of vitamin E that results is restored to its reduced form by ascorbic acid. The dehy-droascorbic acid formed in this process is reconverted to ascorbic acid by interaction with the reduced form of glutathione. Subsequently, oxidized glu-tathione formed in the reaction is reconverted to the reduced form of glu-tathione by glutathione reductase (Fig. 7.6). Vitamins E and C and glutathione are thus intimately linked in antioxidant defence. The interdependence of the various nutritional components of antioxidant defence is illustrated in a study in which healthy subjects were given 500 mg ascorbic acid day-1 for 6 weeks (Johnston et al., 1993). A 47% increase in the glutathione content of red blood cells occurred. Vitamin B6 and riboflavin, which have no antioxidant properties

Methionine

Homocysteine

Cysteine

Vit. E

Oxidants

reduced

Ì

Vit. E

oxidized

Dehydroascorbic acid

Ascorbic acid

Glutathione GSH

tilt

Glutathione GSSG

Glutathione reductase

Riboflavin

Fig. 7.6. The interaction between antioxidants in maintaining antioxidant defence.

per se, also contribute to antioxidant defences indirectly. Vitamin B6 is the cofactor in the metabolic pathway for the biosynthesis of cysteine (Fig. 7.1). Cellular cysteine concentration is rate limiting for glutathione synthesis. Riboflavin is a cofactor for glutathione reductase, which maintains the major part of cellular glutathione in the reduced form (Fig. 7.6).

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