Ascorbylperoxide from parenteral nutrition induces an increase of redox potential of glutathione and loss of alveoli in newborn guinea pig lungs

BACKGROUND: Bronchopulmonary dysplasia is one of the main complications associated with extreme prematurity. Oxidative stress is suspected to be a trigger event of this lung disease, which is characterized by impaired alveolar development. Peroxides, mainly ascorbylperoxide and H(2)O(2), are known contaminant of parenteral nutrition. We hypothesize that these oxidant molecules induce bronchopulmonary dysplasia development. The aim was to determine if the infusion of ascorbylperoxide, whether in presence or absence of H(2)O(2), is associated with oxidative stress, apoptosis and loss of alveoli in the lungs of newborn guinea pigs. METHOD: Three-day-old guinea pigs received parenteral solutions containing 0, 20, 60 or 180 µM ascorbylperoxide in the presence or not of 350 µM H(2)O(2) (concentrations similar to those measured in parenteral nutrition). After 4 days, the lungs were collected for determination of glutathione's redox potential, caspase-3 activation (an apoptosis marker), alveolarization index (by histology), activation of Nrf2 and NF?B (biological markers of oxidative stress), and IL-6 and PGJ(2) levels (markers of NF?B activation). Groups were compared by ANOVA, p < 0.05. RESULTS: Loss of alveoli was associated with ascorbylperoxide in a dose-dependent manner, without an influence of H(2)O(2). The dose-dependent activation of caspase-3 by ascorbylperoxide was lower in the presence of H(2)O(2). Ascorbylperoxide induced an increase of redox potential in a dose-dependent manner, which reached a plateau in presence of H(2)O(2). Nrf2 and NF?B were activated by H(2)O(2) but not by ascorbylperoxide. CONCLUSION: Results suggest that ascorbylperoxide, generated in parenteral nutrition, is involved in the development of bronchopulmonary dysplasia, independently of the increase of the redox potential. This study underlines the importance of developing a safer formulation of parenteral nutrition.