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8. The clinical significance of the role of glutamine in immune cells

Knowledge of the role of glucose for the brain, red blood cells and other tissues has led to an understanding of the significance of the maintenance of a normal blood glucose level, of the complex controls that ensure that the blood glucose level is controlled, and of the clinical importance of hypoglycaemia (NEWSHOLME and LEECH, 1983). Similar considerations can be brought to bear on the significance of maintenance of the plasma glutamine level to ensure its availability for cells of the immune system and other cells such as endothelial cells. The requirement for glutamine will increase dramatically after injury, surgery, infection and burns, since there will be increased activity of the immune system and an increased number of cells will participate in cell division and hence will require glutamine.

It has been known for some time, that the net rate of protein breakdown is increased in injury, sepsis, and particularly in the case of burns. The precise role of this net increase in muscle protein degradation has been unclear; it has been suggested, for example, to be provision of precursor for gluconeogenesis, or for synthesis of important proteins by the liver (acute phase proteins). However, the increased breakdown of muscle protein - in injury, surgery, sepsis and burns appears to be out of proportion compared to these requirements. It is suggested that protein breakdown maintains a pool of available amino acids (e.g., valine, leucine, isoleucine, glutamate, aspartate) which can be transaminated and metabolized in muscle to provide nitrogen for the synthesis of glutamine. And this is to satisfy the large and the increased demand of glutamine for cells of the immune system and others.

The question arises, therefore, as to whether a low rate of degradation of protein could impair the formation of glutamine in muscle and hence lower the plasma level of glutamine so that, in some situations, the response of the immune system to infection could be decreased? The important point to arise from this question is that simply improving nitrogen balance in a patient without maintaining levels of glutamine could be detrimental for the functioning of the immune system. Furthermore, the administration of branched-chain amino acids would not be beneficial in increasing the function of this system, and hence the rate of recovery of patients, unless the muscle glutamine level was very low and synthesis of glutamine was limiting the rate of glutamine release. In this case, branched-chain amino acids could provide nitrogen for the formation of glutamine in muscle (and hence increase the rate of efflux from the muscle, and hence the availability of glutamine for the immune system) and decrease the rate of protein degradation. This may be the case, however, in relatively few conditions. It is more likely that provision of branched-chain amino acids would be of no value to the provisions of glutamine for the immune system, since the transport process for glutamine in muscle is still flux-generating. The limiting factor in the patient is not the synthesis of glutamine, but the rate of release which does not respond adequately to the increased demand for glutamine by the immune system. Nutritional treatment in these patients, it is argued, would need to result in stimulation of glutamine efflux from the muscle as well as its synthesis within the muscle. Such considerations may explain the variability in the effect of provision of branched-chain amino acids on recovery of patients. Since there is little indication how this transport system could be stimulated, at present the best means of improving the glutamine status may be via provision of glutamine enterally or parenterally.

9. The effects of glutamine provision for the patient

The question arises as to how the concentration of glutamine may be manipulated, by dietary or other means, in a way that may be beneficial to the patient. The administration of glutamine to patients poses a number of technical problems. For example, the sterilization and storage procedures routinely employed for parenteral and enteral forms of nutrition may result in acceleration of the degradation of glutamine to glutamate and ammonia, or to the toxic compound, pyroglutamate (see ROTH et al., 1988). Recently, glutamine-containing dipeptides (e.g., alanylglutamine) have been employed, as they represent a more stable form of this amino acid. Studies of the effects of glutamine provision to experimental animals and man have produced encouraging results. It has been shown that glutamine provision corrects or improves the function of some tissues, when that function has been impaired, so far, it has not been shown that glutamine provision can 'boost' the function.

Following is a list of situations in which glutamine provision has been beneficial for the immune system:

- Glutamine in TPN increases the biliary level of IgA, which is normally suppressed by TPN (BURKE et al., 1989).

- The alanine-glutamine dipeptide, given via TPN to tumour-bearing rats, increases the suppressed rate of macrophage phagocytosis (KWEON et al., 1991).

- The alanine-glutamine dipeptide, given via TPN to septic rats, increases the suppressed rate of lymphocyte proliferation and increases the number of lymphocytes (YOSHIDA et al., 1992).

- Glutamine given via intravenous infusion to bone marrow transplant patients decreases the number of positive microbial cultures and decreases the number of clinical infections (SCHELTINGA et al., 1991).

There is also evidence that provision of glutamine can have beneficial effects on other tissues such as muscle and the intestine. For example, glutamine, when given via TPN to normal rats, decreased bacterial translocation from the intestine to the blood, suggesting improved function of the intestine (BURKE et al., 1989); the dipeptide, alanine-glutamine, given via TPN to patients after surgery, restored muscle glutamine levels, increased the decreased rate of muscle protein synthesis, and corrected negative nitrogen balance (HAMMARQVIST et al., 1990; BARUA et al., 1992); and infusion of glutaminecontaining dipeptides in post-operative dogs attenuated or reversed the injury-associated decreases in the concentrations of glutamine in muscle and plasma (ROTH et al., 1988).

Thus, the provision of glutamine to cells of the immune system and other cells involved in tissue repair, via the artificial supplementation of the blood glutamine pool, may provide optimal conditions for the functioning of the body's defence mechanism and repair processes. Furthermore, given the proposed importance of the release of glutamine from skeletal muscle, it is suggested that dietary or pharmacological treatments, which result in an endogenous increase in the rate of muscle glutamine release, may also represent an avenue for successful therapy of a number of pathological states.

10. Branched-point sensitivity, substrate cycles and thermogenesis

Branched-point sensitivity provided by the glutamine pathway in immune cells may be vitally important for control. It is also possible that it expends energy. However, how much energy is expended to maintain such branched-point sensitivity in these cells is not known. Thus, the maintenance of the plasma glutamine concentration via synthesis and release from muscle will require energy but whether branched-point sensitivity imposes a rate of metabolism that is high and energy-demanding, is unclear. Thus, the high rate of glycolysis in tumour cells and in immune cells has been proposed by the author to provide branched-point sensitivity (NEWSHOLME et al., 1985a; b).

The process involves the conversion of glucose to lactate and unless lactate can be completely oxidised by other tissues it will be converted to glucose in liver. The conversion of glucose to lactate in one tissue (immune cells) and re-conversion to glucose in the liver is known as the Cori cycle and is equivalent to a large inter-tissue substrate cycle. It therefore leads to expenditure of energy. Its quantitative importance in energy expenditure is still uncertain, but it may be quite large.

Further work is needed on the fate of the end-products of the glutamine pathway in the immune cells. It is possible that if glutamate, aspartate and alanine, which may be released by immune cells, are reconverted to glutamine in other tissues, such as muscle or liver, the extra energy expenditure required for these biosynthetic processes could be high. It is also possible that only a small proportion is recycled, and most of these end-products are converted to glucose and urea in the liver. This would supply glucose for these tissues and explain why urea excretion may increase under such conditions. If the end-products are not recycled, it may decrease energy requirements, but it will increase the drain on body protein to provide nitrogen for glutamine synthesis.


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