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)：肺表面活性物质是一种表面活性物质 排列在肺泡表面的物质，由-90组成 百分比的脂肪和5-10%的表面活性蛋白质(SF-A、B、C和D)。SF-A 和SP-D是调节表面活性物质的复杂的肺特异性糖蛋白 代谢与肺免疫防御。SP-B和SP-C是短疏水的 蛋白质，负责临床表面活性衍生的表面活性 来自牛和猪的肺。因为天然表面活性剂的制剂各不相同 相当大的蛋白质组成，并可能使受者暴露于免疫原性 蛋白质和病毒污染，我们已经集中在结构和 人SP-B和SP-C合成模拟物的功能特征及 一种标准化、可重复性的受控表面活性剂制剂的设计 组成。患有呼吸窘迫综合征(RDS)的早产儿 肺不成熟致肺表面活性物质缺乏，但功能性表面活性物质 肺表面活性物质在肺泡腔的抑制所致的不足 主要见于成人呼吸窘迫综合征(ARDS)。我们的目标是 设计能抵抗各种抑制作用的合成表面活性剂 与ARDS相关。建议的研究包括设计、合成、 结构表征、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物质制剂 和SP-C模拟肽用于治疗肺表面活性物质缺乏， 表面活性物质抑制和细菌性肺炎。我们建议将这些措施延长 二硫键连接的SP-B和SP-B的合成肽设计 与天然疏水表面活性蛋白相似的SF-C同源二聚体。 由于SP-B和SF-C在体外和体内相互作用，而SP-A降低了 表面活性剂制剂的缓蚀敏感性，我们将对其表面进行评估 人工合成SF-B和SP-C模拟多肽与天然多肽制剂的活性 科幻小说A。总体而言，这些研究将有助于确定和发展 含有肺表面活性物质配方的新型多肽应该是有用的 治疗新生儿RDS的表面活性物质缺乏和抑制 还有ARDS。

项目成果

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants.

• DOI: 10.1159/000451076
• 发表时间: 2016-09
• 期刊: Biomedicine hub
• 作者: Walther FJ;Gordon LM;Waring AJ
• 通讯作者: Waring AJ

Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress.

长期氧化应激诱导的实验性支气管肺发育不良的基因表达谱和组织病理学。

• DOI: 10.1016/j.freeradbiomed.2003.12.007
• 发表时间: 2004
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Wagenaar,GerryTM;terHorst,SimoneAJ;vanGastelen,MargôtA;Leijser,LaraM;Mauad,Thais;vanderVelden,PieterA;deHeer,Emile;Hiemstra,PieterS;Poorthuis,BenJHM;Walther,FransJ
• 通讯作者: Walther,FransJ

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。

• DOI: 10.1152/japplphysiol.00452.2004
• 发表时间: 2004
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: terHorst,SimoneAJ;Wagenaar,GerryTM;deBoer,Eveline;vanGastelen,MargôtA;Meijers,JoostCM;Biemond,BartJ;Poorthuis,BenJHM;Walther,FransJ
• 通讯作者: Walther,FransJ

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。

• DOI: 10.1016/s0006-3495(00)76299-0
• 发表时间: 2000
• 期刊: Biophysical journal.
• 作者: Veldhuizen,EJ;Waring,AJ;Walther,FJ;Batenburg,JJ;vanGolde,LM;Haagsman,HP
• 通讯作者: Haagsman,HP

Lateral stress relaxation and collapse in lipid monolayers.

脂质单层的横向应力松弛和塌陷。

• DOI: 10.1039/b804611e
• 发表时间: 2008
• 期刊: Soft matter
• 影响因子: 3.4
• 作者: Pocivavsek,Luka;Frey,ShelliL;Krishan,Kapilanjan;Gavrilov,Kseniya;Ruchala,Piotr;Waring,AlanJ;Walther,FransJ;Dennin,Michael;Witten,ThomasA;Lee,KaYeeC
• 通讯作者: Lee,KaYeeC