Immunization with Tn Antigen Protects Adult Mice and Newborn Rats against Hyperoxia-Induced Lung Injury via Inhibition of Nuclear Factor-Κb Signaling Pathway

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Acute lung injury is defined as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence for cardiogenic pulmonary edema. Oxygen therapy is often required to treat newborns and adult with respiratory disorders. However, therapy with hyperoxia provided to infants and adult during lung injury not only have beneficial effects but also have adverse long-term effects. Prolonged exposure to hyperoxia at elevated partial pressure leads to inflammation and acute lung injury. The therapeutic strategies of hyperoxia-induced lung injury have been a focus in studies of pediatrics and pulmonary medicine although effective therapies have not been confirmed. Prolonged exposure of neonatal mice to hyperoxia resulted in decreased alveolar and capillary development and increased lung fibrosis, which is similar to human bronchopulmonary dysplasia. Despite early surfactant therapy, optimal ventilator strategies, and increased use of noninvasive positive pressure ventilation, bronchopulmonary dysplasia remains to be a complication of premature births. Bronchopulmonary dysplasia remains a major cause of morbidity and mortality during the first year of life, and many infants experience significant respiratory morbidity. However, no effective therapy is currently clinically available to prevent hyperoxia-induce lung injury and the development of bronchopulmonary dysplasia. Tn antigen is N-acetylgalactosamine (GalNAc) residue that is α-linked to a serine or threonine residue, which is one member of tumor-associated carbohydrate antigens. Tn antigen is a pan-carcinoma antigen, expressed on breast, pancreas, colon, lung, and bladder carcinomas, being less common in hematological malignancies. Tn can induce tumor-specific IgG antibodies in mice and in nonhuman primates under appropriate conditions. These findings raised promise that Tn might be essential components in the design of humoral mediated vaccines. We have found that Tn immunoreactivity in lung tissues is higher in the newborn rats reared in the hyperoxia from postnatal days 1 to 21 than that reared in the room air. Using the Linear Array Epitope technology, the authors have developed an anti-Tn vaccine, which induces anti-Tn antibodies with high specificity and high affinity in mice. These results suggest that Tn may show immunogenicity and protection in animal studies. Hyperoxia increases nuclear factor-κB (NF-κB) translocation in fetal and adult lung fibroblasts and the production of proinflammatory mediators such as tumor necrosis factor-α, interferon-γ, and interleukin-1β. Hyperoxia exposure also increases NF-κB activation in the murine lungs. In this project, we hypothesize that the Tn immunization and anti-Tn antibody administration would attenuate hyperoxia-induced lung injury in adult mice and newborn rats via inhibition of NF-κB signaling pathway. The aims of this project are 1) to investigate the protective effects of Tn immunization on hyperoxia-induced lung injury in adult mice; 2) to investigate the protective effects of prenatal Tn immunization on hyperoxia-induced lung injury in newborn rats; 3) to investigate the protective effects of anti-Tn antibody on hyperoxia-induced lung injury in newborn rats; and 4) To explore the mechanisms that mediate the protective effects of Tn immunization in hyperoxia-induced lung injury in adult mice and newborn rats.
StatusFinished
Effective start/end date8/1/177/31/18

Keywords

  • hyperoxia
  • lung injury
  • Tn antigen
  • immunization
  • cytokine
  • nuclear factor-κB