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（由申请人提供）：吸入有毒化学物质在肺部的主要生理作用是支气管收缩和肺水肿。尽管这些作用是充分理解的，但缺乏特定的解毒剂限制了先前治疗干预措施的有效性。由于表面活性剂失活和自由基的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物质的大鼠中进行测试合成表面活性剂。合成表面活性剂具有大规模生产和较长的保质期的优势，并且可以很容易地适应以优化对失活的耐药性。我们的实验室已经设计，合成和表征了几种高度活跃的表面活性剂蛋白B（SP-B）和C（SP-C）模拟物（Mini-B，Super-Mini-B，Maxi-B和Sp-CFF）作为当前在Neonatal呼吸遇险遇险窘迫综合症（RDS）中使用的天然肺表面活性剂制剂的合成替代方法。在合成肺灌洗脂质和耐磷脂酶耐药磷脂酰胆碱（例如磷酸二酚，例如DEPN-8）中制定的这些合成表面活性剂蛋白模拟物正在接受急性RDS（ARDS）的有用性，这在急性RDS（ARDS）中有用，这具有许多具有肺损伤的肺部受损高度毒性化学物质的特征。该应用的具体目的是：i）合成和表征新型的合成表面活性剂模仿蛋白和耐磷脂酶耐药的磷脂脂，设计为具有较高的脂质结合，表面活性和抑制性； ii）测试通过暴露于剧毒剧烈气体（例如氯）或液体（例如盐酸）引起的急性肺损伤大鼠中优化表面活性剂制剂的体内功效。这些特定目标将使用一套集成的技术套件来实现，包括SP-B和C的肽构建体的合成； 2D-NMR的SP-B和C肽的溶液结构； SP-B和C肽和蛋白质的单层和多层FTIR残基特异性结构研究；通过圈养的气泡表面测量法表征这些构建体在合成表面活性剂脂质中的表征；以及在表面活性剂失活条件下，使用氯/盐酸大鼠模型估计实验表面活性剂对肺功能的体内功效。这些研究应促进合成表面活性剂混合物的发展，以治疗吸入的有毒化学物质引起的ARDS。项目叙述：吸入有毒化学物质会导致气道损害，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。外源表面活性剂疗法可以作为肺水肿的解毒剂，我们建议在暴露于氯气或盐酸之后，开发新的合成表面活性剂对抑制和氧化应激的耐药性，并在暴露于氯气或盐酸的大鼠中测试它们。