Background Uteroplacental insufficiency in humans is a common prenatal insult that leads to intrauterine growth restriction (IUGR), prolonged need for supplemental oxygen, and a predisposition toward dysregulated alveolar formation. Dysregulation of alveolar formation is manifest morphologically by thickened mesenchyme. Using our rat model of uteroplacental insufficiency-induced IUGR, we have previously presented that IUGR increases both perinatal and postnatal pulmonary p53 gene expression in association with dysregulated alveolar formation. p53 is a well studied transcription factor that regulates apoptosis and cell cycle regulation, key processes in alveolar formation.
Objective With the objective of demonstrating that p53 plays a pivotal role in the dysregulation of alveolar formation, we hypothesized that p53 deficiency blunts the developing lungs' response to hyperoxic stress.
Methods To test this hypothesis, we used the transgenic mice that are p53 deficiency: (C.129S2(B6)-Trp53tm1Tyj/j). To determine if p53 mRNA expression is different in the lungs of p53 transgenic mice, real-time RT-PCR was performed on p53 +/+, +/-, and -/- mouse lungs. In order to evaluate oxygen-induced changes lung histology and morphometry in a developing mouse lung in a p53 dose-dependent manner, p53 transgenic mice (+/+, +/-, -/-) and their dams were exposed to 60% oxygen from DOL 3 to DOL 6, corresponding to initiation of alveolar formation. Lungs were isolated at DOL 21, and morphometric analysis was performed to assess the extent of oxygen-induced alveolar dysregulation (n = 3 litters).
Results We found that p53 -/- lungs contained 3% of the p53 mRNA contained in +/+ lungs, and that p53 +/- lungs contained 41% of the p53 mRNA contained in the +/+ lungs. 60% oxygen increased mesenchyme thickness of the +/- p53 mice (1.70 ± 0.10 μm), whereas the p53 deficiency resulted in a significant decrease in mesenchyme thickness (1.55 ± 0.11* μm; p < .05).
Conclusion We have previously demonstrated that IUGR affects epigenetic characteristics of the p53 gene and causes a persistent increase in p53 gene expression in the IUGR model of dysregulated alveolar formation. We now find that lack of p53 protects the developing lung from oxygen-induced mesenchymal thickening in these transgenic mice. We speculate that p53 plays a pivotal role in the developing lung's response to stress.
University of Utah CHRC and the CHRCDA.
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