MECHANISMS OF SURFACTANT INHIBITION

描述（申请人的摘要）：肺表面活性剂是一种表面活性剂， 衬在肺的肺泡表面的材料，由-90 %的脂质和5- 10%的表面活性蛋白（SF-A、B、C和D）。SF-A 和SP-D是复杂的肺特异性糖蛋白， 代谢和肺免疫防御。SP-B和SP-C是短疏水的 蛋白质，负责临床表面活性剂的表面活性， 从牛和猪肺中提取。由于天然表面活性剂的制备各不相同， 在蛋白质组成中有相当大的差异，并且可能使接受者暴露于免疫原性的 蛋白质和病毒污染，我们专注于结构和 人SP-B和SP-C的合成模拟物的功能特性以及 设计了一种标准化的、可重复的表面活性剂制剂， 混合物.早产儿呼吸窘迫综合征（RDS） 由于肺不成熟导致表面活性剂缺乏，但功能性表面活性剂 肺泡腔内肺表面活性物质抑制所致的缺乏 在成人呼吸窘迫综合征（ARDS）中占主导地位。我们的目标是 设计合成表面活性剂，以抵抗各种类型的抑制 与ARDS有关。建议的研究包括设计，合成， 结构表征以及体外和体内表面活性测试 由磷脂和SP-B组成的合成肺表面活性剂制剂 和SP-C模拟肽，其用于治疗肺表面活性物质缺乏， 表面活性剂抑制和细菌性肺炎。我们建议延长这些 合成肽设计努力合成二硫键连接的SP-B和 SF-C同源二聚体类似于天然疏水表面活性剂蛋白。 由于SP-B和SF-C在体外和体内相互作用，SP-A降低了 表面活性剂制剂的抑制敏感性，我们将评估表面 具有合成SF-B和SP-C模拟肽和天然SF-B和SP-C模拟肽的制剂的活性 SF-A。总的来说，这些研究将有助于确定和发展 新的，含肽的肺表面活性剂制剂， 用于治疗新生儿RDS中的表面活性物质缺乏和表面活性物质抑制 和ARDS。

DESCRIPTION (Applicant's Abstract): Lung surfactant is a surface-active material that lines the alveolar surface of the lung and is composed of -90 percent lipids and 5-10 percent surfactant proteins (SF-A, B, C, and D). SF-A and SP-D are complex, lung-specific glycoproteins which modulate surfactant metabolism and lung immunological defense. SP-B and SP-C are short hydrophobic proteins, responsible for the surface activity of clinical surfactants derived from bovine and porcine lungs. Because natural surfactant preparations vary considerably in protein composition and may expose recipients to immunogenic proteins and viral contamination, we have focused on the structural and functional characteristics of synthetic mimics of human SP-B and SP-C and the design of a standardized, reproducible surfactant preparation of controlled composition. Premature infants with respiratory distress syndrome (RDS) are surfactant deficient due to lung immaturity, but functional surfactant deficiency due to inhibition of lung surfactant in the alveolar space predominates in adult respiratory distress syndrome (ARDS). Our objective is to design synthetic surfactants that will resist various types of inhibition associated with ARDS. The proposed studies include the design, synthesis, structural characterization, and in vitro and in vivo surface activity testing of synthetic lung surfactant formulations composed of phospholipids and SP-B and SP-C mimic peptides for use in the treatment of lung surfactant deficiency, surfactant inhibition, and bacterial pneumonia. We propose to extend these synthetic peptide design efforts to the synthesis of disulfide linked SP-B and SF-C homodimers that are similar to native hydrophobic surfactant proteins. Since SP-B and SF-C interact in vitro and in vivo and SP-A decreases the inhibition sensitivity of surfactant preparations, we will assess the surface activity of formulations with synthetic SF-B and SP-C mimic peptides and native SF-A. Overall, these studies will facilitate the identification and development of novel, peptide containing lung surfactant formulations that should be useful for treating surfactant deficiency and surfactant inhibition in neonatal RDS and ARDS.