The state of lung development at birth is one of the major factors determining death or survival in the neonatal period. Although surfactant deficiency is recognized to cause respiratory distress in preterm infants, the role of abnormal growth of the lungs (this includes blood vessels as well as airways and alveoli) has received little attention. Nevertheless, mortality rates are still high in infants with secondary pulmonary hypoplasia and primary pulmonary hypoplasia is diagnosed only when severe. Many of the structural and functional features of the hypoplastic lung remain poorly defined. The mechanical factors that alter lung volume in utero and cause pulmonary hypoplasia after prolonged leakage of amniotic fluid and renal abnormalities are not known. Although the underlying mechanism(s) responsible for the pulmonary hypoplasia remain obscure, many have suggested that it is secondary to oligohydramnios. Experiments in small animals have shown the oligohydramnios alone does cause pulmonary hypoplasia but the structural and functional features of the lungs as well as the mechanism(s) involved have not been determined. I propose to do experiments with the following objectives: 1) To determine the anatomical, biochemical and physiological effects of oligohydramnios on the fetal respiratory system, 2) To investigate the mechanism(s) responsible for producing pulmonary hypoplasia during oligohydramnios, and 3) To investigate the functional consequences of pulmonary hypoplasia resulting from oligohydramnios in newly born lambs. Quantification of the effects of oligohydramnios alone on lung structure and function is essential as it allows a precise comparison with normal lungs and with lungs following amniocentesis, fetoscopy, and fetal nephrectomy (future studies). The results from the proposed studies will not merely be of interest to the developmental physiologist but may prove of considerable importance for perinatal medicine since it seems probably that procedures such as amniocentesis and fetoscopy which are performed in the second trimester may well impair lung development.
