EFFECTS OF PHYSICAL STIMULI ON FETAL LUNG DEVELOPMENT

物理刺激对胎儿肺部发育的影响

• 批准号: 6199967
• 负责人: Joseph A. Kitterman
• 金额: $ 30.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-20 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6199967
• 关键词: congenital respiratory disorder; disease /disorder model; embryo /fetus; embryo /fetus chemotherapy; embryo /fetus therapy; embryo /fetus toxicology; glucocorticoids; growth /development; hernia; laboratory rat; nonhuman therapy evaluation; pesticides; respiratory airflow disorder; respiratory airway volume; retinoate; teratogens

During the previous grant period, we focused on (a) effects of lung distention on fetal lung growth and development and (b) apoptosis in the fetal lung. The current project extends our observation on fetal lung distention and relates them to the clinical problem of congenital diaphragmatic hernia (CDH) and new methods of treating CDH prenatally. Congenital anomalies are a leading cause of neonatal death, with pulmonary hypoplasia the most common anomaly in infants dying the neonatal period. CDH, a major cause of pulmonary hypoplasia, occurs once in 2400 births and has a high mortality rate. Fetal lung growth depends primarily on physical, or mechanical factors, which influence lung growth by changes in lung distension, or stretch, a potent stimulus for diverse cellular effects. With CDH, pulmonary hypoplasia results from alteration of several of these factors. Occluding the fetal trachea distends the lung with fluid and stimulates lung growth, findings that have led to clinical efforts to treat CDH prenatally by tracheal occlusion. Although preliminary results have been encouraging, little is known about effects of tracheal conclusion on some aspect of lung development crucial to adequate pulmonary function, including quantitative lung morphology, the pulmonary vasculature, and lung water balance. Also, tracheal occlusion produces potentially adverse effects, such as decreases in surfactant and alveolar type II cells. Administration of the pesticide of the pesticide, nitrofen, to pregnant rats causes CDH and pulmonary hypoplasia in 60% of the fetuses; the condition resembles CDH in human infants. We propose to distend, by tracheal occlusion, the lungs in fetal rats with nitrofen-induced CDH and to study the effects on lung growth and maturation, on differentiation of the distal pulmonary epithelium, on quantitative pulmonary and vascular morphology. on lung water transport and on components of the cytoskeleton, which is involved in cellular transduction of mechanical stimuli. We will also examine effects on maternal (a) glucocorticoids, which accelerate lung maturation, but which may adversely affect septation and lung growth, and of (b) retinoic acid, which postnatally increases septation and reverses the decreased septation due to dexamethasone. We have shown that apoptosis is a normal process in fetal lung development. How3ever, because changes in lung distension have little effect on apoptosis, further studies of that process are not included in the current project. Results of the proposed studies will increase our knowledge of fetal pulmonary biology and provide new information that may have direct bearing on the clinical problem of CDH.

在上一个资助期间，我们重点关注（a）肺扩张对胎儿肺生长和发育的影响以及（b）胎儿肺细胞凋亡。当前的项目扩展了我们对胎儿肺膨胀的观察，并将其与先天性膈疝 (CDH) 的临床问题和产前治疗 CDH 的新方法联系起来。先天性异常是新生儿死亡的主要原因，其中肺发育不全是新生儿期死亡的婴儿最常见的异常。 CDH是肺发育不全的主要原因，每2400名新生儿中就会发生一次，死亡率很高。胎儿肺的生长主要取决于物理或机械因素，这些因素通过肺膨胀或伸展的变化影响肺的生长，肺膨胀或伸展是多种细胞效应的有效刺激。对于 CDH，肺发育不全是由其中几个因素的改变引起的。闭塞胎儿气管会使肺部充满液体并刺激肺部生长，这些发现导致临床努力通过气管闭塞来治疗产前CDH。尽管初步结果令人鼓舞，但关于气管结论对肺发育某些方面的影响知之甚少，这些方面对于足够的肺功能至关重要，包括定量的肺形态、肺脉管系统和肺水平衡。此外，气管阻塞还会产生潜在的不利影响，例如表面活性剂和 II 型肺泡细胞的减少。给怀孕的老鼠施用杀虫剂除草醚，会导致60%的胎儿出现CDH和肺发育不全；这种情况类似于人类婴儿的 CDH。我们建议通过气管闭塞，用除草醚诱导的 CDH 使胎鼠的肺扩张，并研究其对肺生长和成熟、远端肺上皮分化、定量肺和血管形态的影响。影响肺水运输和细胞骨架成分，细胞骨架参与机械刺激的细胞转导。我们还将检查（a）糖皮质激素对母体的影响，糖皮质激素会加速肺成熟，但可能对肺间隔和肺生长产生不利影响，以及（b）视黄酸，它会在出生后增加肺间隔并逆转地塞米松导致的肺间隔减少。我们已经证明细胞凋亡是胎儿肺发育的正常过程。然而，由于肺膨胀的变化对细胞凋亡影响不大，因此当前项目不包括对该过程的进一步研究。拟议研究的结果将增加我们对胎儿肺部生物学的了解，并提供可能对 CDH 临床问题产生直接影响的新信息。