Intrauterine infection induces programmed cell death in rabbit periventricular white matter

An association between chorioamnionitis and periventricular leukomalacia ha s been reported in human preterm infants. However, whether this link is cau sal has not been convincingly established, and the underlying molecular mec hanisms remain unclear. The objective of this study was to establish a repr oducible model of cerebral white matter disease in preterm rabbits after in trauterine infection. Escherichia coli was inoculated into both uterine hor ns of laparotomized pregnant rabbits when gestation was 80% complete. The f etuses were delivered by cesarean section and killed 12, 24, or 48 h after the inoculation. Programmed cell death in the white matter was evaluated by hematoxylin-eosin-saffron staining and in situ fragmented DNA labeling (te rminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). In a first group of 14 pregnant rabbits not treated with antibiotics, all fetuse s delivered 48 h after inoculation were stillborn, whereas fetuses extracte d 12 or 24 h after inoculation were alive. No significant cell death was de tected in the live fetuses compared with the control noninfected rabbits. I n a second group of five pregnant rabbits treated with ceftriaxone initiate d 24 h after the inoculation and continued until cesarean section was perfo rmed 48 h after inoculation, 13 fetuses were alive, but all showed evidence of extensive programmed cell death in the white matter by hematoxylin-eosi n-saffron staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. White matter damage became histologically detectable onl y 48 h after inoculation. Three of the 13 brains displayed periventricular white matter cysts mimicking human cystic periventricular leukomalacia. The high reproducibility of white matter damage in our model should permit fur ther studies aimed at unraveling the molecular mechanisms of periventricula r leukomalacia.