Hypoxia-induced intrauterine growth retardation: effects on pulmonary development and surfactant protein transcription

Background and objectives: Preterm infants with intrauterine growth retardation (IUGR) reveal an increased risk for the development of acute and chronic pulmonary disorders, i.e. bronchopulmonary dysplasia (BPD). In order to investigate the effect of IUGR on pulmonary development, an easily reproducible animal model for fetal growth restriction has been established using hypoxia as a sole intervention in the last third of pregnancy.

Methods: Date-mated mice were randomly assigned to either being kept at a fraction of inspired oxygen (FiO2) of 0.10 (hypoxic group) starting at day 14 or under normoxic conditions until day 17.5 of gestation (control group). Variables of somatic growth were assessed and standardized histomorphometric analyses of pulmonary tissue were performed. Expression of surfactant proteins (SP)-A, -B, -C and -D was determined by quantitative rt-PCR as biochemical indicators for lung development and maturation.

Results: Fetuses were delivered preterm at 0.87 of gestation. Those grown under hypoxic conditions revealed significantly lower birth weights (median: 0.69 vs. 0.97 g in controls; p < 0.001), body lengths (median: 17.5 vs. 20.2 mm in controls; p < 0.001) and fronto-occipital diameters (median: 9.4 vs. 10.1 mm in controls; p < 0.001) compared to controls. Histomorphometric analyses were found to be without significant differences between both groups. On the transcriptional level, however, mRNA expression of SP-A, -B and -C but not SP-D could be shown to be significantly reduced in hypoxic fetuses compared to normoxic controls.

Conclusions: In conclusion, hypoxic conditions from day 14 to 17.5 led to IUGR in preterm mice and to significant alterations of the developing surfactant system. We speculate restricted development of SP gene expression to be a causal factor for the increased risk of acute and chronic pulmonary disorders in preterm infants with IUGR.