Abstract
Hyperoxia therapy is often required to treat newborns with respiratory disorders. Prolonged hyperoxia exposure increases oxidative stress and arrests alveolar development in newborn rats. Tn antigen is N-acetylgalactosamine residue that is one of the most remarkable tumor-associated carbohydrate antigens. Tn immunization increases the serum anti-Tn antibody titers and attenuates hyperoxia-induced lung injury in adult mice. We hypothesized that maternal Tn immunizations would attenuate hyperoxia-induced lung injury through the suppression of oxidative stress in neonatal rats. Female Sprague–Dawley rats (6 weeks old) were intraperitoneally immunized five times with Tn (50 μg/dose) or carrier protein at biweekly intervals on 8, 6, 4, 2, and 0 weeks before the day of delivery. The pups were reared in room air (RA) or 2 weeks of 85% O2, creating the four study groups: carrier protein + RA, Tn vaccine + RA, carrier protein + O2, and Tn vaccine + O2. The lungs were excised for oxidative stress, cytokine, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) expression, and histological analysis on postnatal day 14. Blood was withdrawn from dams and rat pups to check anti-Tn antibody using western blot. We observed that neonatal hyperoxia exposure reduced the body weight, increased 8-hydroxy-2-deoxyguanosine (8-OHdG) expression and lung cytokine (interleukin-4), increased mean linear intercept (MLI) values, and decreased vascular density and VEGF and PDGF-B expressions. By contrast, Tn immunization increased maternal and neonatal serum anti-Tn antibody titers on postnatal day 14, reduced MLI, and increased vascular density and VEGF and PDGF-B expressions to normoxic levels. Furthermore, the alleviation of lung injury was accompanied by a reduction in lung cytokine and 8-OHdG expression. Therefore, we propose that maternal Tn immunization attenuates hyperoxia-induced lung injury in neonatal rats through the suppression of oxidative stress and inflammation.
Highlights
Respiratory distress syndrome is a major cause of morbidity and mortality in preterm neonates [1]
Representative lung sections stained with hematoxylin and eosin and von Willebrand factor (vWF) from maternal Tn immunization and postnatal hyperoxia-exposed rats on postnatal day 14 are shown in Figures 4A,B, respectively
Our in vivo model revealed that maternal Tn immunization increased maternal and neonatal serum antibody titers and attenuated hyperoxia-induced lung injury in newborn rats, as evidenced by reversing hyperoxia-induced increase in mean linear intercept (MLI) and decrease in vascular density and growth factors
Summary
Respiratory distress syndrome is a major cause of morbidity and mortality in preterm neonates [1]. The rat model is appropriate to study the effects of hyperoxia on preterm infants with respiratory distress because rats are born at the saccular stage, equivalent to an ∼30 week human gestation [2]. Optimal ventilation strategies, and increased use of noninvasive positive pressure ventilation, bronchopulmonary dysplasia remains a major cause of morbidity and mortality during the first year of life, and many infants experience significant respiratory morbidity, including decreased response to acute hypoxia, increased airway reactivity, and development of obstructive airway disease throughout childhood [5,6,7]. No effective clinical therapy is currently available to prevent the development and long-term pulmonary sequelae of bronchopulmonary dysplasia
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