Morphometric analysis of preterm fetal pulmonary development in the sheep model of congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) in humans carries high mortality/morb idity attributed to associated pulmonary hypoplasia. An understanding of th e effects of CDH on fetal lung groups is important for development of succe ssful treatments. This study aimed to quantitate structural differences bet ween normal and CDH-affected preterm lamb lungs. We hypothesized that (a) p ulmonary hypoplasia is present in preterm CDH-affected lungs; (b) the relat ive degree of pulmonary hypoplasia increases with gestation; and (c) the le ft upper lobe (LUL) is affected most. Fetal lambs were allocated to two groups. One group underwent surgery (72-7 4 days gestation) inducing CDH. Both groups (n = 7, n = 7) were delivered b y cesarean section at 129 days (term: 145-149). Lungs were obtained at auto psy, were inflation-fixed, processed for histology, and morphometry was per formed. 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 mi vs. 96.9 mi); 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 pm), gas-exchan ge 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 m u m; 2003 cm(-1), 0.11 ml/m(2), respectively). The LUL was affected most. These data quantitate pulmonary hypoplasia in preterm CDH-affected lambs. C omparisons with published data indicate increasing relative hypoplasia as g estation proceeds. Fetal interventions will affect lung development, depend ing on timing, with intervention still, likely to be worthwhile during late gestation.