Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: Possible application for congenital diaphragmatic hernia

Abstract

Pulmonary hypoplasia has a definite clinical impact in a variety of congenital diseases such as renal dysplasia and congenital diaphragmatic hernia. These diseases have in common inadequate growth and development of fetal lungs. Previous reports have demonstrated increased lung growth with in utero tracheal ligation. The purpose of this study was to determine if lung growth can be accelerated in the setting of experimental pulmonary hypoplasia. Ninety-five-day gestation fetal sheep were divided into four experimental groups: nephrectomy, nephrectomy with tracheal ligation, tracheal ligation alone, and sham-operated control animals. Animals were delivered near term and their lungs inflation fixed at 25 cm H 2O. Total alveolar number (Alv#), total alveolar surface area (AlvSA), and lung volume to body weight ratios (LV:BW) were determined for apical and basilar segments of each animal and then averaged. Total lung DNA and protein content were also analyzed. The nephrectomy group had smaller lungs than control animals with decreased Alv#, AlvSA, and LV:BW. In contrast, nephrectomy with tracheal ligation produced large lungs which had increased Alv#, AlvSA, and LV:BW when compared with both the nephrectomy and the control group ( P < .01). Total lung DNA and protein concentrations were both markedly elevated in the tracheally obstructed groups. However, the DNA/protein ratios remained constant in all four groups, suggesting that lung growth had occurred through cell multiplication. Photomicrographs of the lung demonstrated a histologically immature appearance in the nephrectomy group and a histologically mature appearance in the tracheally obstructed groups. We conclude: (1) tracheal ligation in the fetus accelerated lung growth beyond normal limits; (2) fetal tracheal ligation accelerates lung growth even in the absence of fetal kidneys; (3) lung growth is achieved at least in part by cell proliferation rather than hypertrophy; (4) histologically, fetal lung architecture remains relatively normal, suggesting that developmental pathways are not markedly disordered by tracheal ligation; and (5) pulmonary hypoplasia associated with congenital diaphragmatic hernia also appears to be prevented by these manipulations.