BAPS prize-1999: Lung growth induced by prenatal tracheal occlusion and its modifying factors: a study in the rat model of congenital diaphragmatic hernia

BACKGROUND/PURPOSE: Prenatal tracheal occlusion (TO) has been shown to accelerate lung growth in animal models and models of pulmonary hypoplasia. However, these models may not mimic early events in human congenital diaphragmatic hernia (CDH). The authors previously have developed a model of TO in the rat. The purpose of this study was to apply this technique to characterize TO-induced lung growth in the early onset nitrofen-induced model of CDH, and to address the clinically important questions of the effect of timing of TO and maternal infusion of terbutaline on TO-induced lung growth. METHODS: Left-sided CDH was induced in the fetuses of time-dated pregnant Sprague-Dawley rats by feeding 100 mg of nitrofen on day 9 of gestation. TO was performed via maternal laparotomy and hysterotomy at 19 days' gestation. At harvest (21.5 days' gestation), lungs from nitrofen-exposed fetuses without CDH (non-CDH), with CDH (CDH), and with CDH and TO (CDH-TO) were compared by analysis of wet and dry weight, DNA and protein content, and stereologic morphometry. A second study was performed to assess relative lung growth achieved by equal intervals of TO after "early" (19 days) versus "late" (20 days) gestational TO. Finally, the effect of maternal infusion of terbutaline, a commonly used tocolytic for fetal surgery, on TO-induced lung growth was analyzed. RESULTS: Analysis of lung growth showed consistent and significant lung growth in CDH-TO lungs. Lung growth after TO was proliferative and characterized by an increase in parenchymal volume as manifest by increased total saccular number and surface area and radial saccular count. Although visceral reduction was partially achieved, herniated liver was reduced incompletely. The majority of lung growth occurred during the latter half of the TO period. Early gestational age at TO and maternal terbutaline administration adversely influenced lung growth in CDH-TO fetuses. CONCLUSIONS: Prenatal TO induces dramatic lung growth in the early onset, nitrofen-induced rat model of CDH. TO is more effective later in gestation presumably because of the advanced stage of lung development and lung fluid production. This effect could be counterbalanced by the use of beta-mimetic tocolytic, which inhibits fetal lung fluid production late in gestation. Multiple factors including fetal lung fluid production and absorption, pharmacologic agents, space-occupying herniated viscera, and timing and duration of TO may be important clinical variables. The development of the rat model should facilitate further studies into the cellular and molecular mechanisms responsible for TO-induced lung growth.