SURFACTANT PROTEIN A GENE AND ITS REGULATION

支气管肺发育不良(BPD)是急性肺的并发症。 与新生儿呼吸窘迫综合征(RDS)和 它的治疗方法。尽管外源表面活性剂的普遍使用 对早产儿的治疗大大减轻了RDS的严重程度，并 出生体重为1000克的婴儿的死亡率， 肺表面活性物质治疗在降低心绞痛发生率方面的作用不大。 每桶。BPD和相关肺损伤的发生率进一步降低 要求制定产前和/或产后治疗方案，以 外源性表面活性物质促进肺成熟及增强效应的研究 心理治疗。天然肺表面活性物质制剂含有表面活性蛋白， SP-B和SP-C，但缺乏SP-A，这是一种主要的表面活性蛋白 与表面活性磷脂一起被发育调节。 SP-A似乎有助于降低肺泡表面张力，从而 介导II型细胞重摄取表面活性物质，以阻断表面活性物质 血清蛋白灭活作用与增强体内免疫功能 肺泡。早产、通风的狒狒提供了一种 BPD病因学及其治疗研究的极佳模型。在……里面 考虑到SP-A在表面活性物质作用中的潜在重要性， 临床批准的含有SP-B的外源表面活性物质中不存在该物质 和SP-C，它们在预防BPD方面相对无效， 建议对狒狒SP-A基因(S)及其转录产物进行特征分析 胎儿和出生后早期发育的调节。在预赛中 研究发现，在恒河猴胎肺组织中，SP-A基因表达水平明显高于正常对照组。 培养受cAMP、糖皮质激素和氧气的调节 与人类相似，如果不是完全相同的话。循环AMP导致明显的 诱导SP-A基因表达，而地塞米松引起剂量依赖关系 抑制SP-A基因的表达。我们还获得了证据表明 狒狒SP-A由单拷贝基因编码。基因组克隆已经被 含有狒狒SP-A基因和~gt；6kb 5‘-侧翼的分离株 区域。在拟议的研究中，表达的发育变化 SP-A基因及其转录本，以及在cAMP的作用下， 糖皮质激素和氧气对恒河猴胎肺SP-A基因表达的影响 将对文化进行调查。被发现可以促进肺成熟和 SP-A基因表达将在出生后给药至早产 与外源表面活性物质相结合的分娩狒狒；疗效 这些减轻RDS和BPD严重程度的治疗方法将与 外源表面活性剂单独作用的效果。此外，还将进行研究，以 定义发展和发展过程中涉及的顺式作用要素 猴胎肺SP-A基因表达的多因素调控 研究肺核蛋白结合的发育性变化 这些区域。我们认为，对基本机制的理解 参与SP-A基因表达的调节将导致 促进肺表面活性物质产生的治疗方法的发展 早产婴儿和，防止有害的影响 机械通风和氧气导致BPD。

Bronchopulmonary dysplasia (BPD) develops as a complication of acute lung injury associated with neonatal respiratory distress syndrome (RDS) and its therapy. Although the prevalent use of exogenous surfactant for treatment of premature infants has greatly reduced the severity of RDS and the mortality rate of infants with birthweights of <1,000 grams, surfactant therapy has only a modest effect to reduce the incidence of BPD. Further reductions in the incidence of BPD and associated lung injury require development of antenatal and/or postnatal therapeutic regimens to enhance lung maturation and augment effects of exogenous surfactant therapy. Natural lung surfactant preparations Contain surfactant proteins, SP-B and SP-C, but lack SP-A, a major surfactant protein that is developmentally regulated in association with surfactant phospholipids. SP-A appears to facilite the reduction of alveolar surface tension, to mediate surfactant reuptake by type II cells, to block the surfactant inactivating effects of serum proteins and enhance immune function within the alveolus. The prematurely born, ventilated baboon provides an excellent model for study of the etiology of BPD and its treatment. In consideration of the potential importance of SP-A in surfactant function, its absence from clinically approved exogenous surfactants containing SP-B and SP-C, which are relatively ineffective in preventing BPD, it is proposed to characterize the baboon SP-A gene(s), its mRNA transcripts and regulation during fetal and early postnatal development. In preliminary studies, we found that SP-A gene expression in baboon fetal lung in culture is regulated by cAMP, glucocorticoids and oxygen in a manner that is similar, if not identical, to the human. Cyclic AMP causes a marked induction of SP-A mRNA levels, whereas, Dex causes a dose-dependent inhibition of SP-A mRNA accumulation. We also have obtained evidence that baboon SP-A is encoded by a single copy gene. Genomic clones have been isolated that contain the baboon SP-A gene and >6 kb of 5'-flanking region. In the proposed studies, developmental changes in expression of the SP-A gene and its transcripts, and in the effects of cAMP, glucocorticoids and oxygen on SP-A gene expression in baboon fetal lung in culture will be investigated. Agents found to enhance lung maturation and SP-A gene expression will be administered postnatally to prematurely delivered baboons in combination with exogenous surfactant; efficacy of these treatments to reduce severity of RDS and BPD will be compared to effects of exogenous surfactant alone. Studies also will be implemented to define the cis-acting elements involved in the developmental and multifactorial regulation of SP-A gene expression in baboon fetal lung and to study developmental changes in the binding of lung nuclear proteins to these regions. It is our view that understanding of basic mechanisms involved in regulation of SP-A gene expression will lead to the development of therapies to accelerate pulmonary surfactant production in prematurely born infants and, prevent the deleterious effects of mechanical ventilation and oxygen resulting in BPD.