Synthetic surfactant and toxic chemical lung injury

描述（由申请人提供）：吸入有毒化学品对肺的主要生理作用是支气管收缩和肺水肿。虽然这些影响是很好的理解，缺乏具体的解毒剂限制了以前的治疗干预的有效性。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，我们建议在暴露于高毒性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长保质期的优点，并且可以容易地调整以优化对失活的抗性。本实验室设计、合成并表征了几种高活性表面活性蛋白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）的天然肺表面活性制剂的合成替代品。这些合成的表面活性剂蛋白模拟物配制在合成的肺灌洗液脂质和抗磷脂酶磷脂酰胆碱（膦酰脂质，例如DEPN-8）中，正在研究其在急性RDS（ARDS）中的有效性，其具有吸入高毒性化学品继发性肺损伤的许多特征。本申请的具体目的是：i）合成和表征设计成具有高脂质结合、表面活性和抑制抗性的新型合成表面活性剂模拟蛋白和磷脂酶抗性膦酰基脂质;和ii）测试优化的表面活性剂制剂在具有由暴露于高毒性气体（例如，氯）或液体（例如，盐酸）。这些具体目标将使用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肽和蛋白质的单层和多层FTIR残基特异性结构研究;通过捕获气泡表面测量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/盐酸大鼠模型来评估在表面活性剂失活的条件下实验表面活性剂对肺功能的体内功效。这些研究将促进合成表面活性剂混合物的发展，用于治疗吸入有毒化学品引起的ARDS。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。外源性表面活性剂治疗可以作为肺水肿的解毒剂，我们建议开发新的合成表面活性剂抗抑制和氧化应激，并在暴露于氯气或盐酸后患有危及生命的呼吸系统疾病的大鼠中进行测试。

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.