Maternal undernutrition during pregnancy causes intrauterine growth restriction (IUGR) of fetus. Alterations in fetal nutritional status may result in developmental adaptations that permanently change the structure and physiology of the offspring, thus predisposing individuals to pulmonary, endocrine, and cardiovascular diseases in adult life. This phenomenon termed “fetal programming” has led to the theory of fetal origins of adult disease. IUGR has been shown to associate with reduced lung function during infancy and perhaps throughout adulthood. Numerous studies have found a range of general cellular and molecular effects of IUGR on the developing lung, including reduced lung weight, DNA or protein content, and impaired alveolization. Supplemental oxygen administered to newborn infants with respiratory failure can increase oxidant stress and lead to lung injury. IUGR is considered an independent risk factor for the development of later bronchopulmonary dysplasia because IUGR markedly altered the fetal lung structure and cellular dysfunction. These findings provide compelling evidence for the fetal origins of bronchopulmonary dysplasia. Epigenetics is genetic modifications that result in changes in gene expression and function without a corresponding alteration in DNA sequence. Epigenetic mechanisms include DNA methylation, covalent histone modifications, and noncoding RNAs. Epidemiological studies have shown that IUGR is associated with an increased incidence of pulmonary, cardiovascular, and metabolic disorders in later life in humans. A growing body of evidence suggests that the intrauterine environment has a significant and lasting effect on the long-term health of the growing fetus and the development of lung diseases in later life. We have found that maternal undernutrition during the last week of gestation affects lung morphometry and surfactant protein and insulin-like growth factor expression in the rat offspring. Insulin-like growth factor system has altered epigenetic states in response to IUGR. Identification of the specific epigenetic mechanisms involved in the developmental origin of lung disease is important to assist identification of molecular biomarkers with the potential to identify respiratory disease risk factors and treatment in childhood. Receptors for advanced glycation end-products (RAGE) are members of the immunoglobulin superfamily of cell-surface receptors. Soluble RAGE (sRAGE) is a competitive, negative regulator of membrane RAGE activation. We have found that the decreased sRAGE expression of after postnatal hyperoxia and the expressions were further decreased after maternal systemic inflammation and postnatal hyperoxia. However, the effects of IUGR and/or hyperoxia on RAGE were not known. Animal models have provided a very useful source in the clarification of the outcomes and mechanisms elicited during developmental programming. The aims of this study are: (1) to establish a perinatal double-hit model of bronchopulmonary dysplasia by maternal uteroplacental insufficiency and postnatal hyperoxia exposure in neonatal rats; (2) to examine the combined effects of maternal uteroplacental insufficiency and neonatal hyperoxia exposure on lung development, epigenetic alterations, and RAGE signaling pathways in the rat offspring; (3) to identify the specific epigenetic mechanisms involved in the developmental origin of lung disease; (4) to evaluate the effects of recombinant sRAGE on rat lungs exposed to maternal uteroplacental insufficiency and/or neonatal hyperoxia.
|Effective start/end date||8/1/14 → 7/31/15|
- uteroplacnetal insufficiency
- bronchopulmonary dysplasia
- receptor for advanced glycation end products