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: 6609134
• 负责人: Joseph A. Kitterman
• 金额: $ 8.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6609134
• 关键词: congenital respiratory disorder; disease /disorder model; embryo /fetus; embryo /fetus chemotherapy; embryo /fetus therapy; embryo /fetus toxicology; glucocorticoids; hernia; laboratory rat; lung development; 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.

在上一个赠款期间，我们专注于（a）肺扩张对胎儿肺部生长和发育的影响以及（b）胎儿肺中的凋亡。当前的项目扩展了我们对胎儿肺扩张的观察结果，并将其与先天性diaphragmatic疝（CDH）的临床问题和新的CDH产前治疗方法联系起来。先天性异常是新生儿死亡的主要原因，肺部发育不全是死于新生儿时期的婴儿最常见的异常。 CDH是肺动脉低下的主要原因，在2400个出生中一次发生一次，死亡率很高。胎儿肺的生长主要取决于物理或机械因素，这些因素或机械因素会因肺延伸的变化或拉伸而影响肺的生长，这是多种细胞作用的有效刺激。使用CDH，肺动脉迟缓是由于其中几个因素的改变而导致的。闭塞胎儿气管通过液体延伸肺并刺激肺部生长，发现导致临床努力通过气管阻塞治疗CDH。尽管初步结果令人鼓舞，但对气管结论对肺发育的某些方面的影响鲜为人知，这对适当的肺功能至关重要，包括定量肺形态，肺脉管系统和肺水平衡。同样，气管闭塞会产生潜在的不良反应，例如表面活性剂和牙槽II型细胞的降低。给予农药的硝基素农药给怀孕的大鼠，导致60％的胎儿引起CDH和肺动脉粥样硬化。该疾病类似于人类婴儿的CDH。我们建议通过气管阻塞扩大胎儿大鼠中硝基蛋白诱导的CDH的肺，并研究对肺部生长和成熟的影响，对肺部远端肺上皮的分化，对定量肺和血管形态的分化。在肺水转运和细胞骨架的成分上，与机械刺激的细胞转导有关。我们还将检查对母体（a）糖皮质激素的影响，这些糖皮质激素会加速肺部成熟，但可能会对分离和肺部生长和（b）视黄酸产生不利影响，这会在产后增加分离并逆转由于地塞米松而导致的分离。我们已经证明凋亡是胎儿肺发育中的正常过程。 How3ever，由于肺延伸的变化对凋亡几乎没有影响，因此对该过程的进一步研究不包括在当前项目中。拟议研究的结果将增加我们对胎儿肺生物学的了解，并提供可能与CDH临床问题有关的新信息。