MECHANISMS OF SURFACTANT INHIBITION

表面活性剂抑制机制

• 批准号: 6845144
• 负责人: FRANCISKUS JOHANNES WALTHER
• 金额: $ 29.56万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845144
• 关键词: disease /disorder model; hydropathy; inhibitor /antagonist; intermolecular interaction; laboratory rabbit; laboratory rat; newborn animals; peptide chemical synthesis; phospholipids; protein structure function; pulmonary surfactants; respiratory distress syndrome of newborn; respiratory gas level; surface property; synthetic peptide

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.

描述（申请人摘要）：肺表面活性剂是一种表面活性物质 排列在肺泡表面的材料，由 -90 组成 % 脂质和 5-10% 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，可调节表面活性剂 代谢和肺免疫防御。 SP-B和SP-C是短疏水性的 蛋白质，负责临床表面活性剂衍生的表面活性 来自牛和猪的肺。由于天然表面活性剂制剂各不相同 蛋白质组成显着变化，并可能使受体暴露于免疫原性 蛋白质和病毒污染，我们重点关注结构和 人 SP-B 和 SP-C 的合成模拟物的功能特征及其 设计标准化、可重复的表面活性剂制剂 作品。患有呼吸窘迫综合征（RDS）的早产儿 由于肺不成熟而缺乏表面活性剂，但功能性表面活性剂 由于肺泡腔内肺表面活性物质的抑制而导致的缺乏 在成人呼吸窘迫综合征（ARDS）中占主导地位。我们的目标是 设计能够抵抗各种类型抑制的合成表面活性剂 与 ARDS 相关。拟议的研究包括设计、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模拟肽用于治疗肺表面活性物质缺乏症， 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 同二聚体与天然疏水性表面活性剂蛋白相似。 由于 SP-B 和 SF-C 在体外和体内相互作用，而 SP-A 会降低 表面活性剂制剂的抑制敏感性，我们将评估表面 含有合成 SF-B 和 SP-C 模拟肽以及天然肽的制剂的活性 SF-A。总体而言，这些研究将有助于识别和开发 新型含肽肺表面活性剂制剂应该有用 用于治疗新生儿 RDS 中的表面活性剂缺乏和表面活性剂抑制 和急性呼吸窘迫综合征。

项目成果

Multilayer formation upon compression of surfactant monolayers depends on protein concentration as well as lipid composition. An atomic force microscopy study.

表面活性剂单层压缩后的多层形成取决于蛋白质浓度以及脂质组成。

• 发表时间: 2002-06-14
• 作者: Diemel, Robert V;Snel, Margot M E;Waring, Alan J;Walther, Frans J;van Golde, Lambert M G;Putz, Günther;Haagsman, Henk P;Batenburg, Joseph J
• 通讯作者: Batenburg, Joseph J

Dimeric N-terminal segment of human surfactant protein B (dSP-B(1-25)) has enhanced surface properties compared to monomeric SP-B(1-25).

与单体 SP-B(1-25) 相比，人表面活性剂蛋白 B (dSP-B(1-25)) 的二聚体 N 末端片段具有增强的表面特性。

• 发表时间: 2000-07
• 作者: Veldhuizen, E J;Waring, A J;Walther, F J;Batenburg, J J;van Golde, L M;Haagsman, H P
• 通讯作者: Haagsman, H P

Pentoxifylline reduces fibrin deposition and prolongs survival in neonatal hyperoxic lung injury.

己酮可可碱可减少新生儿高氧性肺损伤的纤维蛋白沉积并延长生存期。

• 发表时间: 2004-11
• 作者: ter Horst, Simone A J;Wagenaar, Gerry T M;de Boer, Eveline;van Gastelen, Margôt A;Meijers, Joost C M;Biemond, Bart J;Poorthuis, Ben J H M;Walther, Frans J
• 通讯作者: Walther, Frans J

Functional importance of the NH2-terminal insertion sequence of lung surfactant protein B.

肺表面活性蛋白 B 的 NH2 末端插入序列的功能重要性。

• 发表时间: 2010-03
• 作者: Frey, Shelli L;Pocivavsek, Luka;Waring, Alan J;Walther, Frans J;Hernandez;Ruchala, Piotr;Lee, Ka Yee C
• 通讯作者: Lee, Ka Yee C

Addition of alpha1-antitrypsin to surfactant improves oxygenation in surfactant-deficient rats.

在表面活性剂中添加 α1-抗胰蛋白酶可改善表面活性剂缺乏大鼠的氧合作用。

• 发表时间: 1999-03
• 影响因子: 24.7
• 作者: Belai, Y;Hernández;Bruni, R;Waring, A J;Walther, F J
• 通讯作者: Walther, F J