PATHOGENESIS OF PULMONARY HYPOPLASIA IN CHONDRODYSTROPHY

长期以来，新生儿肺发育不良一直被观察到 与横隔疝、羊水过少等相关 结构畸形。虽然肺发育不全 一般反映肺：体重比较低而塌陷 导致呼吸窘迫的肺泡，准确的序列 导致这种经常致命的疾病的发育事件 仍然不为人知。在实验动物中，肺发育不良 由实验引起的胎儿瘫痪，梗阻 气管和尿路，以及羊水的清除。 这些实验虽然有启发意义，但也有其局限性。 在小鼠中，一种影响软骨形成的遗传性条件 骨骼系统与呼吸窘迫有关 刚出生的。在三个这样的系统上进行的初步实验 突变提示肺发育不良是病因学上的 与呼吸窘迫有关。我们建议对这些问题进行研究 突变和一种药物诱导的软骨营养不良 确定它们是否符合作为动物模型的标准 肺发育不全。形态测量，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儿将 检查生长、成熟和一般情况的差异 肺的发育。具体地说，来自 将对软骨营养不良胎儿进行检查，以确定 整体大小；肺泡扩张；DNA、蛋白质和磷脂 内容；以及薄壁组织的成熟(II型细胞 差异化)。胸部体积、大小和胸围的差异 气管的结构、呼吸道分支的程度和容量 羊水的含量将与以下研究一起确定 发育不良肺的发育史。器官培养 从早期胎儿中分离出的肺将提供一个机会 确定是否涉及与胸围限制无关的因素 改变了肺部的生长和发育。这些实验将 服务于更全面地确定肺证 自发发展的动物模型中的发育不全。这个 拟议研究的目的是为设计提供基础 以增加我们对这一机制的理解 治疗人类的这种疾病。

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.