Maternal Tn Immunization Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats Through Suppression of Oxidative Stress and Inflammation

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% O 2 , creating the four study groups: carrier protein + RA, Tn vaccine + RA, carrier protein + O 2 , and Tn vaccine + O 2 . 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 Blood was withdrawn from dams and rat pups to check anti-Tn antibody using western blot.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.

Anti-Tn Monoclonal Antibody Attenuates Hyperoxia-Induced Lung Injury by Inhibiting Oxidative Stress and Inflammation in Neonatal Mice

“…We revealed that maternal immunization with Tn vaccine increased neonatal rat serum levels of anti-Tn antibody; reduced mean linear intercept (MLI), lung cytokine stress, and oxidative stress; and increased vascular density and growth factor expressions to normoxic levels in hyperoxia-injured neonatal rats (Chen et al, 2019). These findings suggest that anti-Tn antibody has therapeutic effects on rats with hyperoxia-induced lung injury.…”

“…In this study, we evaluated the protective effects of anti-Tn monoclonal antibody on alveolar and vascular development in newborn mice exposed to hyperoxia. We demonstrated that hyperoxia increased oxidative stress and inflammation and led to impaired alveolarization and angiogenesis in neonatal rat lungs (Chen et al, 2019). Consequently, we chose a comparable model and demonstrated hyperoxia affected mice angiogenesis in a similar way.…”

“…In our previous study, we found that maternal immunization with Tn vaccine increased maternal and neonatal serum anti-Tn antibody titers and attenuated hyperoxia-induced lung injury in newborn rats (Chen et al, 2019). However, immunizing mothers to treat premature birth-related lung diseases is impractical because prematurity is clinically unpredictable and unavoidable.…”

“…These results indicate that the administration of anti-Tn monoclonal antibody improved hyperoxia-induced lung injury through increasing VEGF expression. In neonatal rats, prolonged exposure to hyperoxia increases lung cytokine expression and induces inflammation (Chen et al, 2019). The rise in pro-inflammatory cytokines upregulates cell adhesion molecules, increases chemotactic proteins that attract the inflammatory cells into the lung, and leads to the increase of NF-kB (Shahzad et al, 2016).…”

Human placenta-derived mesenchymal stem cells attenuate established hyperoxia-induced lung injury in newborn rats

“…1 Prolonged exposure of neonatal rats to hyperoxia was reported to result in decreased alveolarization and vascularization similar to those in human bronchopulmonary dysplasia. 2,3 The pathogenesis of BPD is multifactorial, and oxygen toxicity is considered to play a crucial role in the lung injury process that leads to BPD development. 4,5 Currently, no effective therapy is clinically available for treating established lung injury induced by hyperoxia.…”