Glutathione Homeostasis & Oxidant Damage in Kwashiorkor

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Severe childhood under nutrition (SCU) presents either as marasmus, kwashiorkor, or marasmic- kwashiorkor. While wasting characterizes all syndromes, in kwashiorkor and marasmic-kwashiorkor (edematous SCU), gross edema, lower plasma proteins, flaky paint dermatitis, impaired immune and anti- oxidant capacities, are among additional features that contribute to an increased morbidity and slower recovery. We have found that compared to children with marasmus, children with edematous SCU have slower fluxes of cysteine and its precursor methionine because of decreased release from a slower protein breakdown. We propose that decreased availability of these two sulfur amino acids (SAAs) contribute to the pathogenesis of certain clinical features and hence, the slower recovery of children with edematous SCU. Studies will be performed in 6-18 mo. old children with SCU to achieve the following specific aims. Specific aim #1 will determine the SAA requirements of children with edematous and non-edematous SCU during the metabolic stabilization and early catch-up growth phases of rehabilitation. Hypothesis tested: In the acutely malnourished state, a slower protein breakdown in children with edematous SCU relative to those with non- edematous SCU results in decreased availability of SAAs. Hence, dietary SAAs supply for replenishment of metabolic capacity and anabolic drive will be greater in children with edematous SCU. Specific aim #2 will determine the splanchnic extraction of dietary SAAs in children with edematous and non-edematous SCU. Hypothesis tested: Because cysteine is a major component of Gl mucins and mucosal glutathione (GSH), a reduction in endogenous SAA production means that the gut requirement, hence splanchnic extraction of dietary SAAs will be greater in children with edematous SCU. Specific aim #3 a&b will determine the effect of dietary supplementation with either a mixture of SAAs or alanine (controls) on small intestine structure, integrity and function, skin epidermal protein synthesis, rate of resolution of skin lesions and recovery of immune capacity in groups of age- and gender-matched children with edematous SCU. Hypotheses tested: During the early phase of rehabilitation, supplementation of the resuscitative diet with adequate amounts of SAAs will stimulate synthesis rates of gut mucosal and digestive enzymes proteins, mucosal GSH and skin epidermal protein to a greater extent than in alanine controls, thereby restoring small intestine structure, and function and resolution of skin lesions earlier. Similarly, faster normalization of GSH synthesis will facilitate earlier restoration of immune function. This research may explain whether a shortage of two special compounds called sulfur amino acids is responsible for the severe illness and high death rate of children with the kwashiorkor type of malnutrition and whether supplying adequate amounts of these compounds in the treatment diet will speed up recovery.