Synthetic surfactant and toxic chemical lung injury

合成表面活性剂和有毒化学品肺损伤

基本信息

批准号：
7526492
负责人：
FRANCISKUS JOHANNES WALTHER
金额：
$ 30.34万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7526492
关键词：
Acute Acute Lung Injury Acute respiratory failure Adult Respiratory Distress Syndrome Albumins Alveolar Amino Acids Amyloid Animals Antidotes Binding Blood capillaries Breathing Bronchoalveolar Lavage Bronchoconstriction C-Peptide Characteristics Chemical Surfactants Chemicals Chlorine Circular Dichroism Clinical Computer Simulation Condition Curosurf Data Development Dose Drug Formulations Edema Effectiveness Esters Ethers Ethyl Ether Exhibits Exposure to Extravasation Family Fibrinogen Film Fourier Transform Free Radical Formation Free Radicals Functional disorder Gases Hazardous Chemicals Histology Hydrochloric Acid Hydrolysis Infasurf Investigation Laboratories Lead Lecithin Life Link Lipid Binding Lipids Liquid substance Lung Lung diseases Mass Spectrum Analysis Measures Mechanics Methods Modeling Monitor Mucous Membrane Newborn Respiratory Distress Syndrome Nitrogen Oxidative Stress Oxygen Pathway interactions Peptide Synthesis Peptides Phosphatidyl glycerol Phosphatidylglycerols Phospholipase Phospholipids Physiological Poison Post-Translational Protein Processing Preparation Production Property Proteins Pulmonary Edema Pulmonary Surfactant-Associated Protein B Pulmonary Surfactants Range Rattus Resistance Respiratory physiology Secondary to Solutions Spectroscopy, Fourier Transform Infrared Stress Tests Structure Surface Techniques Testing Therapeutic Intervention Work analog capillary chlorine gas design improved in vivo inhibitor/antagonist irritation lung injury monolayer novel peptide B phosphonolipids research study respiratory restoration surfactant synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): The major physiologic actions of inhaled toxic chemicals on the lung are bronchoconstriction and pulmonary edema. Although these effects are well understood, the absence of specific antidotes has limited the effectiveness of prior therapeutic interventions. As surfactant inactivation and the formation of free radicals are important pathways in acute lung injury and edema, we propose testing synthetic surfactant in rats exposed to highly toxic chemicals. Synthetic surfactant has the advantage of large-scale production and a long shelf-life, and may be readily adapted to optimize resistance against inactivation. Our laboratory has designed, synthesized and characterized several highly-active surfactant protein B (SP-B) and C (SP-C) mimics (mini-B, super-mini-B, maxi-B, and SP-Cff) as a synthetic alternative for the natural lung surfactant preparations currently used in neonatal respiratory distress syndrome (RDS). These synthetic surfactant protein mimics formulated in synthetic lung lavage lipids and phospholipase-resistant phosphatidylcholine (phosphonolipids, e.g. DEPN-8) are under investigation for usefulness in acute RDS (ARDS), which shares many characteristics of lung injury secondary to inhaled highly toxic chemicals. The specific aims of this application are to: i) synthesize and characterize novel synthetic surfactant mimic proteins and phospholipase-resistant phosphonolipids designed to have high lipid binding, surface activity and inhibition resistance; and ii) to test the in vivo efficacy of an optimized surfactant preparation in rats with acute lung injury induced by exposure to highly toxic gases (e.g., chlorine) or liquids (e.g., hydrochloric acid). These specific aims will be accomplished using an integrated suite of techniques, including the synthesis of peptide constructs of SP-B and C; solution structure of the SP-B and C peptides by 2D-NMR; monolayer and multilayer FTIR residue-specific structural studies of SP-B and C peptides and proteins; characterization of the surface activity of these constructs in synthetic surfactant lipids by captive bubble surfactometry; and the use of the chlorine/ hydrochloric acid rat model to estimate in vivo efficacy of experimental surfactant on lung function under conditions of surfactant inactivation. These studies should facilitate the development of a synthetic surfactant mixture for treatment of ARDS induced by inhaled toxic chemicals. PROJECT NARRATIVE: Inhalation of toxic chemicals leads to airway damage, bronchoconstriction and severe lung edema secondary to surfactant inhibition and free radical formation. Exogenous surfactant therapy can function as an antidote for lung edema and we propose to develop new synthetic surfactants resistant against inhibition and oxidative stress and test these in rats with life-threatening respiratory disease after exposure to chlorine gas or hydrochloric acid.

描述（申请人提供）：吸入有毒化学物质对肺部的主要生理作用是支气管收缩和肺水肿。尽管这些作用已被充分理解，但缺乏特异性解毒剂限制了先前治疗干预的有效性。由于表面活性剂失活和自由基形成是急性肺损伤和水肿的重要途径，因此我们建议在暴露于剧毒化学品的大鼠中测试合成表面活性剂。合成表面活性剂具有大规模生产和保质期长的优点，并且可以很容易地进行调整以优化对失活的抵抗力。我们的实验室设计、合成并表征了几种高活性表面活性剂蛋白 B (SP-B) 和 C (SP-C) 模拟物（mini-B、super-mini-B、maxi-B 和 SP-Cff）作为目前用于新生儿呼吸窘迫综合征（RDS）的天然肺表面活性剂制剂的合成替代品。这些合成肺灌洗脂质和抗磷脂酶磷脂酰胆碱（磷脂，例如 DEPN-8）中配制的合成表面活性蛋白模拟物正在研究其在急性 RDS (ARDS) 中的用途，该疾病具有吸入剧毒化学品继发的肺损伤的许多特征。本申请的具体目标是： i) 合成并表征新型合成表面活性剂模拟蛋白和抗磷脂酶磷脂，其设计具有高脂质结合、表面活性和抗抑制性； ii) 测试优化的表面活性剂制剂对因暴露于剧毒气体（例如氯）或液体（例如盐酸）而引起急性肺损伤的大鼠的体内功效。这些具体目标将通过一套综合技术来实现，包括 SP-B 和 C 肽构建体的合成；通过 2D-NMR 分析 SP-B 和 C 肽的溶液结构； SP-B 和 C 肽及蛋白质的单层和多层 FTIR 残基特异性结构研究；通过捕获气泡表面活性测定法表征合成表面活性剂脂质中这些构建体的表面活性；以及使用氯/盐酸大鼠模型来估计实验性表面活性剂在表面活性剂失活条件下对肺功能的体内功效。这些研究应有助于开发合成表面活性剂混合物，用于治疗吸入有毒化学品引起的急性呼吸窘迫综合征。项目叙述：吸入有毒化学物质会导致气道损伤、支气管收缩和继发于表面活性剂抑制和自由基形成的严重肺水肿。外源性表面活性剂疗法可以作为肺水肿的解毒剂，我们建议开发新型合成表面活性剂，以抵抗抑制和氧化应激，并在暴露于氯气或盐酸后患有危及生命的呼吸道疾病的大鼠中进行测试。