Synthetic Lung Surfactant Optimized for Biomedical Application

针对生物医学应用优化的合成肺表面活性剂

• 批准号: 8043616
• 负责人: FRANCISKUS JOHANNES WALTHER
• 金额: $ 32.94万
• 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: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043616
• 关键词: Acute; Acute Lung Injury; Adult; Adult Respiratory Distress Syndrome; Affect; Albumins; Alveolar; Amino Acid Substitution; Amino Acids; Animals; Binding; Blood Vessels; Blood capillaries; Bronchoalveolar Lavage; Burn Trauma; C-terminal; Charge; Chemical Surfactants; Child; Childhood; Circular Dichroism; Clinical; Computer Simulation; DNA Insertion Elements; Data; Disease; Drug Formulations; Edema; Engineering; Environmental air flow; Extravasation; Family; Fibrinogen; Film; Free Radicals; Functional disorder; Gases; Generations; Histology; Hypochlorous Acid; Inflammation; Laboratories; Lecithin; Life; Lipase; Lipid Binding; Lipids; Lipopolysaccharides; Lung; Lung diseases; LytA enzyme; Mass Spectrum Analysis; Measures; Mechanics; Methods; Monitor; N-terminal; Nitrites; Nonesterified Fatty Acids; Oleic Acids; Oryctolagus cuniculus; Oxidative Stress; Patients; Peptides; Phosphatidyl glycerol; Phosphatidylglycerols; Phospholipase; Phospholipase A2; Plasma Proteins; Pneumonia; Post-Translational Protein Processing; Premature Infant; Preparation; Property; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; Quality Control; Reactive Oxygen Species; Reproducibility; Resistance; Respiratory physiology; Secondary to; Sepsis; Serum Proteins; Spectroscopy, Fourier Transform Infrared; Stomach; Structure; Surface; Testing; analog; animal disease transmission; base; capillary; cost; crosslink; design; effective therapy; improved; in vivo; inhibitor/antagonist; interstitial; intravenous administration; large scale production; novel; phosphonolipids; prevent; research study; respiratory distress syndrome; restoration; surfactant; synthetic peptide

DESCRIPTION (provided by applicant): Animal-derived surfactant preparations are highly effective in preventing and treating respiratory distress syndrome (RDS) in premature infants, but not in pediatric and adult patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Effective therapy for ALI/ARDS will probably require synthetic surfactant with maximal surface activity and the ability to resist surfactant inhibition due to vascular leakage and acute inflammation. Such synthetic preparations offer the advantages of large-scale production, compositional reproducibility, easier quality control, stability with a long shelf-life, no transmission of animal disease, and lower costs. Synthetic surfactants also allow the use of novel protein and lipid components that may be more inhibition-resistant and possess biophysical properties that outperform native surfactant formulations than are presently available. Our laboratory has designed, synthesized, and characterized several highly-active analogs of surfactant protein B (SP-B), such as "Mini-B" (i.e., cross-linked construct of the N- and C-terminal domains of SP-B) and "Super Mini-B" (i.e., Mini-B with an insertion sequence at the N-terminus), and observed that Super-Mini-B further enhances the surface activity of synthetic surfactant preparations over that seen with native SP-B proteins. Mixing these SP-B analogs in non-toxic phospholipase-resistant lipids, i.e. phosphonolipid analogs of dipalmitoyl phosphatidylcholine (DPPC) and phosphatidylglycerol (PG), will promote inhibition resistance. The specific aims of this proposal are to (1) re-engineer, synthesize and characterize novel synthetic SP-B analogs designed to have high lipid-binding, surface activity and resistance to inhibition and oxidative stress in (phospholipase-resistant) lipid mixtures, and (2) define the in vivo efficacy of synthetic surfactants in rabbits with oleic acid- or lipopolysaccharide (LPS)-induced acute lung injury. We hypothesize that additional re-engineering of Mini-B and Super Mini-B, based on using discrete amino acid substitutions, will maximize their respective lipid binding and surface activity, and also increase their resistance to inhibition and oxidative stress. Formulation of these re-engineered SP-B analogs in phospholipase-resistant lipid mixtures may deliver a synthetic surfactant preparation uniquely able to treat ALI/ARDS. PROJECT NARRATIVE. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening respiratory diseases, which affect children and adults with sepsis, pneumonia, gastric aspiration, burns, trauma, and other acute illnesses. Survival depends on assisted ventilation, treatment of the underlying disease, and reversal of surfactant inhibition in the lung. Re-engineering of the essential surfactant protein B and the predominant lipids to enhance resistance to inhibition and oxidative stress may deliver a synthetic surfactant preparation uniquely able to treat ALI/ARDS.

描述（由申请人提供）：动物衍生的表面活性剂制剂在预防和治疗早产儿的呼吸遇险综合征（RDS）方面非常有效，但在儿科和成年患者急性肺损伤（ALI）和急性呼吸遇险遇险综合征（ARDS）中却没有。对ALI/ARD的有效治疗可能需要具有最大表面活性的合成表面活性剂，并且由于血管渗漏和急性炎症而抗拒表面活性剂抑制作用的能力。这种合成制剂提供了大规模生产，构图可重现性，更容易的质量控制，稳定性，具有长长的保质期，没有动物疾病的传播以及较低的成本的优势。合成表面活性剂还允许使用新型的蛋白质和脂质成分，它们可能更具抑制作用，并且具有比目前可用的生物物理特性胜过本机表面活性剂制剂的生物物理特性。我们的实验室已经设计，合成和表征了表面活性剂蛋白B（SP-B）的几种高度活跃的类似物，例如“ mini-b”（即SP-B）和“超级mini-b”的N-和C末端结构域的交联构建体）和“超级mini-b”（即具有n-termi senterion intermition intermity in n-termi internity intermine and ner-termi），并在n-tern-ternimus上进行了超级超级友好的效果。与天然SP-B蛋白看到的表面活性剂制剂。将这些SP-B类似物混合在抗磷脂酶耐药性脂质中，即二硫米粉酰磷脂酰胆碱（DPPC）和磷脂酰甘油（PG）的磷酸脂类似物（PG），将促进抑制抗性。该建议的具体目的是（1）重新设计，合成和表征新型的合成SP-B类似物，旨在具有高脂质结合，表面活性和对抑制和抗氧化应激（磷脂酶抗磷脂酶的脂质混合物）中的抑制作用和抗氧化应激，以及（2）与合成的酸性酸酸或合成的酸性酸酸性酸含量，（2）脂多糖（LPS）诱导的急性肺损伤。我们假设基于使用离散的氨基酸取代的Mini-B和Super Mini-B的额外重新设计将最大程度地提高其各自的脂质结合和表面活性，并增加其对抑制和氧化应激的抵抗力。这些在耐磷脂酶抗脂质混合物中的重新设计的SP-B类似物的配方可能会提供合成的表面活性剂制剂，以便能够独特地处理ALI/ARDS。项目叙述。急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是威胁生命的呼吸道疾病，会影响儿童和成人患有败血症，肺炎，胃抽吸，烧伤，创伤，创伤和其他急性疾病。存活取决于辅助通风，治疗潜在疾病以及肺部表面活性剂抑制作用的逆转。重新设计必需表面活性剂蛋白B和主要脂质以增强对抑制和氧化应激的耐药性，可能会产生合成的表面活性剂制剂，以独特地治疗ALI/ARDS。

项目成果

Synthetic lung surfactant reduces alveolar-capillary protein leakage in surfactant-deficient rabbits.

• DOI: 10.3109/01902148.2015.1024354
• 发表时间: 2015-06
• 期刊: Experimental lung research
• 影响因子: 1.7
• 作者: Gupta R;Hernández-Juviel JM;Waring AJ;Walther FJ
• 通讯作者: Walther FJ

Synthetic lung surfactants containing SP-B and SP-C peptides plus novel phospholipase-resistant lipids or glycerophospholipids.

含有 SP-B 和 SP-C 肽以及新型磷脂酶抗性脂质或甘油磷脂的合成肺表面活性剂。

• DOI: 10.7717/peerj.2635
• 发表时间: 2016
• 期刊: PeerJ
• 影响因子: 2.7
• 作者: Notter,RobertH;Gupta,Rohun;Schwan,AdrianL;Wang,Zhengdong;Shkoor,MohanadGh;Walther,FransJ
• 通讯作者: Walther,FransJ

Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide.

• DOI: 10.7717/peerj.1528
• 发表时间: 2016
• 期刊: PeerJ
• 影响因子: 2.7
• 作者: Notter RH;Wang Z;Walther FJ
• 通讯作者: Walther FJ

Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats.

• DOI: 10.1111/apha.12622
• 发表时间: 2016-03
• 期刊: Acta physiologica (Oxford, England)
• 作者: Chen X;Walther FJ;van Boxtel R;Laghmani EH;Sengers RM;Folkerts G;DeRuiter MC;Cuppen E;Wagenaar GT
• 通讯作者: Wagenaar GT

Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary Inflammation.

• DOI: 10.3389/fphys.2017.00486
• 发表时间: 2017
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Chen X;Orriols M;Walther FJ;Laghmani EH;Hoogeboom AM;Hogen-Esch ACB;Hiemstra PS;Folkerts G;Goumans MTH;Ten Dijke P;Morrell NW;Wagenaar GTM
• 通讯作者: Wagenaar GTM