PATHOGENESIS OF PULMONARY HYPOPLASIA IN CHONDRODYSTROPHY

新生儿肺发育不全在中国已被观察到

Pulmonary hypoplasia in the neonate has long been observed in association with diaphragmatic hernia, oligohydramnios and other structural malformations. Although pulmonary hypoplasia generally reflects a lower lung:body weight ratio and collapsed alveoli which lead to respiratory distress, the precise sequence of developmental events leading to this frequently lethal disorder remains unknown. In laboratory animals, lung hypoplasia has been experimentally induced by paralysis of the fetus, obstruction of the trachea and urinary tract, and removal of amniotic fluid. These experiments, while instructive, have their limitations. In mice, a hereditary condition of chondrogenesis affecting the skeletal system is associated with respiratory distress of the newborn. Preliminary experiments performed on three such mutants suggest that pulmonary hypoplasia is etiologically involved in the respiratory distress. We propose to examine these mutants and a drug-induced form of chondrodystrophy to determine if they meet the criteria as animal models of pulmonary hypoplasia. With morphometric, histological, ultrastructural and biochemical procedures, day 13-18 chondrodystrophic and unaffected control fetuses will be examined for differences in growth, maturation and general development of the lungs. Specifically, lungs from chondrodystrophic fetuses will be examined for differences in overall size; alveolar expansion; DNA, protein and phospholipid content; and maturation of the parenchyma (type II-cell differentiation). Differences in thoracic volume, size and structure of the trachea, extent of airway branching, and volume of amniotic fluid will be determined in conjunction with studies on the developmental history of the hypoplastic lungs. Organ culture of lungs isolated from early fetuses will provide an opportunity to define if factors independent of thoracic restriction are involved in altered lung growth and development. These experiments will serve to determine more completely the syndrome pulmonary hypoplasia in a spontaneously developed animal model. The objective of the proposed study is to provide a basis for the design of future studies to increase our understanding of the mechanism for this disorder in humans.