PATHOGENESIS OF PULMONARY HYPOPLASIA IN CHONDRODYSTROPHY

新生儿肺发育不全长期以来一直被观察到， 与腹股沟疝、羊水过少和其他 结构畸形 虽然肺发育不全 通常反映出较低的肺：体重比， 肺泡导致呼吸窘迫的确切顺序， 导致这种经常致命的疾病的发展事件 仍然未知。 在实验室动物中，肺发育不全已经被证实是一种 通过胎儿麻痹、梗阻 气管和泌尿道以及羊水的排出。 这些实验虽然有指导意义，但也有其局限性。 在小鼠中，软骨形成的遗传性条件影响 骨骼系统与呼吸窘迫有关， 新生儿 在三个这样的实验中进行了初步实验 突变体表明肺发育不全在病因上是 与呼吸窘迫有关 我们建议研究这些 突变体和药物诱导形式的软骨营养不良， 确定它们是否符合作为动物模型的标准， 肺发育不全 形态学，组织学， 超微结构和生化程序，第13-18天 软骨营养不良和未受影响的对照胎仔将 检查生长、成熟和一般 肺的发育。 具体来说， 将检查软骨营养不良胎儿在以下方面的差异： 整体大小;肺泡扩张; DNA、蛋白质和磷脂 内容;和薄壁组织（II型细胞）的成熟 差异化）。 胸腔容积、大小和 气管的结构、气道分支的范围和体积 将结合以下研究来确定羊水量： 肺发育不良的发展史 器官培养 从早期胎儿分离的肺将提供一个机会， 确定是否涉及与胸廓限制无关的因素 改变肺部的生长和发育 这些实验将 有助于更全面地确定肺综合征 在自发发育的动物模型中的发育不全。 的 建议研究的目的是为设计提供依据 未来的研究，以增加我们对机制的理解 for this disorder疾病in humans人类.

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.