GLUTATHIONE HOMEOSTASIS & OXIDANT DAMAGE IN KWASHIORKOR

严重蛋白质-能量营养不良（PEM）的消瘦综合征治疗简单，死亡率低，而夸希奥克尔(K)和消瘦-夸希奥克尔（MK）综合征很难治疗，死亡率高，因为它们的免疫和器官功能受损更严重。有证据表明，主要抗氧化剂谷胱甘肽（GSH）的浓度在K和MK中较低，但在消瘦症中没有，因此有人提出，由于抗氧化能力受损，氧化剂会导致K和MK儿童器官和组织的细胞损伤。然而，抗氧化能力实际受损的程度、这种受损的原因、与氧化损伤的关系以及与K和MK的免疫和病理生理紊乱的程度的关系尚未确定。本研究提出以下假设：1)在PEM的K和MK综合征中，由于GSH合成受损，氧化损伤增加；2)GSH合成速率较慢是继发于其前体半胱氨酸和甘氨酸的可用性降低；3)这些GSH前体的短缺是由于新生合成减少和全身蛋白质分解速率较慢。iv)在早期营养康复期间膳食补充半胱氨酸和甘氨酸将允许谷胱甘肽合成和供应的更快正常化，从而减少氧化损伤；v)谷胱甘肽合成和浓度的更快正常化将与免疫功能、水肿和肝脏脂肪减少率的平行改善有关。使用生化和稳定同位素示踪方法，这些假设将在6-18个月的PEM婴儿中进行测试。第一个实验方案将确定以下方面的差异：1)红细胞谷胱甘肽、半胱氨酸和甘氨酸的合成速率，2)全身蛋白质分解率，3)血浆中脂质氢过氧化物和偏和正酪氨酸的浓度，氧化损伤指标，消瘦婴儿，K和MK在入院时（研究1），代谢稳定后（研究2）和恢复时（研究3）。第二个实验方案将确定补充半胱氨酸和甘氨酸对这些结果变量的影响，以及对患有K和MK的儿童中谷胱甘肽合成和浓度、淋巴细胞功能以及水肿和肝脂肪减少率之间的关系的影响。获得的数据将有助于了解K和MK的抗氧化能力受损的程度。它与氧化损伤的关系，以及旨在补充抗氧化能力的治疗方法是否会加速PEM的临床和代谢恢复。

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.