GLUTATHIONE HOMEOSTASIS & OXIDANT DAMAGE IN KWASHIORKOR

点击翻译按钮获取中文摘要

Whereas the marasmus syndrome of severe protein-energy- malnutrition (PEM) is simple to treat and has a low mortality rate, the kwashiokor (K) and marasmic-kwashiorkor (MK) syndromes are difficult to treat and have high mortality rates because they have more greatly impaired immune and organ functions. Based on evidence that the concentrations of glutathione (GSH), a major anti-oxidant, are lower in K and MK, but not in marasmus, it has been proposed that oxidants cause cell damage in the organs and tissues of children with K and MK because of impaired antioxidant capacity. However, the extent to which antioxidant capacity is actually impaired, the cause of such an impairment, and the relationships to oxidant damage and to the degree of immunological and patho-physiological derangements of K and MK have not been determined. The research proposed addresses the following hypotheses: i) that in the K and MK syndromes of PEM there is an increase in oxidative damage because of compromised GSH synthesis, ii) that the slower GSH synthesis rate is secondary to decreased availability of its precursors cysteine and glycine, iii) that the shortage of these GSH precursors is due to both decreased de novo synthesis and slower whole body protein breakdown rate, iv) that dietary supplementation with cysteine and glycine during early nutritional rehabilitation will permit faster normalization of GSH synthesis and supply thereby reducing oxidative damage, v) that faster normalization of GSH synthesis and concentration will be associated with parallel improvements in immune function and rates of loss of edema and liver fat. Using biochemical and stable isotope tracer methods, these hypotheses will be tested in 6-18 mo old infants with PEM. The first experimental protocol will determine differences in 1) the rates of synthesis of erythrocyte GSH, cysteine and glycine, 2) whole body protein breakdown rate, 3) the plasma concentrations of lipid hydroperoxides and meta-and ortho- tyrosine, indicators of oxidative damage, between infants with marasmus, K and MK at admission (study 1), after metabolic stabilization (study 2) and at recovery (study 3). The second experimental protocol will determine the effect of cysteine and glycine supplementation on these outcome variables and on the relationships between GSH synthesis and concentration, lymphocyte function and the rate of loss of edema and liver fat in children with K and MK. The data obtained will provide insight into the the extent to which anti-oxidant capacity is impaired in K and MK, its relationship to oxidant damage and whether therapeutic approaches aimed to replenish antioxidant capacity will accelerate clinical and metabolic recovery from PEM.