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: 7586222
• 负责人: FRANCISKUS JOHANNES WALTHER
• 金额: $ 32.34万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586222
• 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; Spectroscopy, Fourier Transform Infrared; Stomach; Structure; Surface; Testing; abstracting; analog; animal disease transmission; base; capillary; cost; crosslink; design; effective therapy; human TYRP1 protein; 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（由申请方提供）：动物源性表面活性剂制剂可高效预防和治疗早产儿呼吸窘迫综合征（RDS），但对急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的儿科和成人患者无效。有效治疗ALI/ARDS可能需要具有最大表面活性的合成表面活性剂，并能够抵抗由于血管渗漏和急性炎症引起的表面活性剂抑制。这种合成制剂提供了大规模生产、组成再现性、更容易的质量控制、具有长保质期的稳定性、不传播动物疾病和较低成本的优点。合成表面活性剂还允许使用新的蛋白质和脂质组分，所述蛋白质和脂质组分可能更具抗抑制性并且具有优于天然表面活性剂制剂的生物物理性质。我们的实验室已经设计、合成和表征了表面活性蛋白B（SP-B）的几种高活性类似物，例如“迷你-B”（即，SP-B的N-和C-末端结构域的交联构建体）和“超级迷你-B”（即，在N-末端具有插入序列的Mini-B），并观察到Super-Mini-B进一步增强了合成表面活性剂制剂的表面活性，超过了天然SP-B蛋白所见的表面活性。将这些SP-B类似物混合在无毒的磷脂酶抗性脂质中，即二棕榈酰磷脂酰胆碱（DPPC）和磷脂酰甘油（PG）的膦酰脂质类似物，将促进抑制抗性。本提案的具体目的是（1）重新设计、合成和表征新型合成SP-B类似物，其设计为在（抗磷脂酶）脂质混合物中具有高脂质结合、表面活性和抑制和氧化应激抗性，以及（2）确定合成表面活性剂在油酸或脂多糖（LPS）诱导的急性肺损伤家兔中的体内疗效。我们假设，额外的重新设计的迷你-B和超级迷你-B，基于使用离散的氨基酸取代，将最大限度地提高各自的脂质结合和表面活性，也增加了他们的抑制和氧化应激的阻力。将这些再工程化的SP-B类似物配制在抗磷脂酶脂质混合物中可以递送独特地能够治疗ALI/ARDS的合成表面活性剂制剂。项目叙述。急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是危及生命的呼吸道疾病，会影响儿童和成人的败血症、肺炎、胃吸入、烧伤、创伤和其他急性疾病。生存取决于辅助通气、基础疾病的治疗和肺表面活性物质抑制的逆转。对必需的表面活性蛋白B和主要脂质进行再工程改造以增强对抑制和氧化应激的抗性，可以提供独特地能够治疗ALI/ARDS的合成表面活性剂制剂。