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Morphometric analysis of preterm fetal pulmonary development in the sheep model of congenital diaphragmatic hernia
J Lipsett1, J C Cool, S I Runciman
1Department of Histopathology, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.
Insights
Congenital diaphragmatic hernia (CDH) causes pulmonary hypoplasia in preterm lambs, significantly reducing lung growth and gas-exchange capacity. Interventions during fetal development may still be beneficial, even in late gestation.
Area of Science:
- Developmental biology
- Fetal surgery
- Pulmonary medicine
Background:
- Congenital diaphragmatic hernia (CDH) is associated with high mortality due to pulmonary hypoplasia.
- Understanding CDH's impact on fetal lung development is crucial for effective treatments.
- Previous studies suggest CDH impairs lung growth, but quantitative data in relevant models are needed.
Purpose of the Study:
- To quantitatively assess structural differences in lungs between normal and CDH-affected preterm lambs.
- To test the hypotheses that pulmonary hypoplasia is present in CDH lambs, worsens with gestation, and most affects the left upper lobe (LUL).
- To provide data informing the timing of fetal interventions for CDH.
Main Methods:
- CDH was surgically induced in fetal lambs at 72-74 days gestation.
- Lambs (n=7 per group) were delivered at 129 days gestation.
- Lungs were inflation-fixed, processed for histology, and underwent morphometric analysis.
Main Results:
- CDH-affected lungs showed significantly reduced lung weight, lung volume, and gas-exchange surface area compared to controls.
- Pulmonary hypoplasia in CDH lambs involved increased non-parenchymal connective tissue, smaller and more numerous airspaces, and reduced capillary volume.
- The left upper lobe (LUL) was disproportionately affected, and data suggest hypoplasia increases with gestational progression.
Conclusions:
- This study quantifies significant pulmonary hypoplasia in preterm lambs with CDH, confirming impaired lung development.
- The findings support the hypothesis that CDH negatively impacts fetal lung growth, with increasing severity as gestation advances.
- Fetal interventions for CDH, even later in gestation, may still offer benefits for lung development.
Abstract:
Congenital diaphragmatic hernia (CDH) in humans carries high mortality/morbidity attributed to associated pulmonary hypoplasia. An understanding of the effects of CDH on fetal lung growth is important for development of successful treatments. This study aimed to quantitate structural differences between normal and CDH-affected preterm lamb lungs. We hypothesized that (a) pulmonary hypoplasia is present in preterm CDH-affected lungs; (b) the relative degree of pulmonary hypoplasia increases with gestation; and (c) the left upper lobe (LUL) is affected most. Fetal lambs were allocated to two groups. One group underwent surgery (72-74 days gestation) inducing CDH. Both groups (n = 7, n = 7) were delivered by cesarean section at 129 days (term: 145-149). Lungs were obtained at autopsy, were inflation-fixed, processed for histology, and morphometry was performed. Preterm lungs of CDH-affected lambs in comparison to those of normal lambs demonstrated a reduction in the following: lung weight (37.7 g vs. 116.3 g); lung weight:body weight (0.012 vs. 0.040); fixed lung volume (33.6 ml vs. 96.9 ml); gas-exchange surface area (4.56 m(2) vs. 13.70 m(2)); parenchyma:nonparenchyma (59:41 vs. 72:28); and parenchymal airspace:tissue (16:84 vs. 35:65). Non-parenchyma connective tissue was increased (58%), airspaces were more numerous (1077/mm(2)) and smaller (perimeter 76.6 microm), gas-exchange surface density (2394 cm(-1)) was greater and capillary loading (0.04 ml/m(2)) was reduced compared to preterm normal lung (49%; 778/mm(2); 108.7 microm; 2003 cm(-1), 0.11 ml/m(2), respectively). The LUL was affected most. These data quantitate pulmonary hypoplasia in preterm CDH-affected lambs. Comparisons with published data indicate increasing relative hypoplasia as gestation proceeds. Fetal interventions will affect lung development, depending on timing, with intervention still likely to be worthwhile during late gestation.
