Dose–Response Effects of Glutathione Supplement in Parenteral Nutrition on Pulmonary Oxidative Stress and Alveolarization in Newborn Guinea Pig

Abstract

In premature infants, glutathione deficiency impairs the capacity to detoxify the peroxides resulting from O2 metabolism and those contaminating the parenteral nutrition (PN) leading to increased oxidative stress, which is a major contributor to bronchopulmonary dysplasia (BPD) development. In animals, the supplementation of PN with glutathione prevented the induction of pulmonary oxidative stress and hypoalveolarization (characteristic of BPD). Hypothesis: the dose of glutathione that corrects the plasma glutathione deficiency is sufficient to prevent oxidative stress and preserve pulmonary integrity. Three-day-old guinea pigs received a PN, supplemented or not with GSSG (up to 1300 µg/kg/d), the stable form of glutathione in PN. Animals with no handling other than being orally fed constituted the control group. After 4 days, lungs were removed to determine the GSH, GSSG, redox potential and the alveolarization index. Total plasma glutathione was quantified. The effective dose to improve pulmonary GSH and prevent the loss of alveoli was 330 µg/kg/d. A 750 µg/kg/d dose corrected the low-plasma glutathione, high-pulmonary GSSG and oxidized redox potential. Therefore, the results suggest that, in a clinical setting, the dose that improves low-plasma glutathione could be effective in preventing BPD development.

Glutathione Supplementation Prevents Neonatal Parenteral Nutrition-Induced Short- and Long-Term Epigenetic and Transcriptional Disruptions of Hepatic H2O2 Metabolism in Guinea Pigs

“…Specifically, for Gpx1 , the addition of GSSG prevented PN-induced gene methylation. These results are consistent with the concept that the addition of GSSG to PN improves tissue GSH levels, which helps detoxify peroxides [ 24 ]. Nguyen et al [ 31 ] also reported the hypermethylation and downregulation of GPx1 in ATX mice, a model used to study the oxidative environments associated with dyslipidemia and atherosclerosis.…”

“…However, this PN does not exist and cannot be produced, as the generation of peroxides is caused by the unavoidable interactions between nutrients [ 8 , 9 , 27 ]. Therefore, the third study group consisted of GSSG-supplemented PN [ 15 , 24 ].…”

“…PN+GSSG : animals fed PN supplemented with 12 μM of GSSG (corresponding to 1.3 mg/kg/d) [ 15 , 24 ].…”

“…As in premature infants [ 21 , 22 ], PN infusion induces glutathione deficiency in animals [ 8 ]. This deficiency was prevented by the addition of disulfide glutathione (GSSG) to their PN [ 24 ]. Both GSSG and GSH are substrates for the gamma-glutamyl cycle, which promotes the intracellular transfer of cysteine from plasma glutathione (GSH or GSSG) with a view to the new cellular synthesis of glutathione [ 25 ].…”

Parenteral Cysteine Supplementation in Preterm Infants: One Size Does Not Fit All

“…The GSSG supplementation of PN made it possible to prevent, in newborn guinea pigs, a deficiency in plasma and pulmonary glutathione [85,86]. By preventing pulmonary oxidative stress, this supplementation has also prevented the pulmonary loss of alveoli [33,37], which is a main characteristic of bronchopulmonary dysplasia observed in premature infants.…”