Synthetic surfactant and toxic chemical lung injury

说明（由申请人提供）：吸入有毒化学物质对肺的主要生理作用是支气管收缩和肺水肿。虽然这些影响已被充分了解，但由于缺乏特异性解毒剂，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，我们建议在暴露于高毒性化学物质的大鼠中测试合成表面活性剂。合成表面活性剂具有生产规模大、保存期长、抗失活能力优化等优点。本实验室设计、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、超mini-B、max -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。这些合成表面活性剂蛋白模拟物是在合成肺灌洗液和抗磷脂酶磷脂酰胆碱（磷脂，如DEPN-8）中配制的，目前正在研究其在急性RDS （ARDS）中的有效性，ARDS具有吸入高毒性化学物质引起的肺损伤的许多特征。本申请的具体目的是：i)合成和表征新型合成表面活性剂模拟蛋白和抗磷脂酶的磷脂，设计具有高脂结合，表面活性和抗抑制性；ii)在暴露于剧毒气体（如氯）或液体（如盐酸）引起的急性肺损伤大鼠中，测试一种优化的表面活性剂制剂的体内疗效。这些具体目标将通过一套集成的技术来实现，包括SP-B和C的肽结构的合成；SP-B和C肽溶液结构的二维核磁共振分析SP-B和C肽和蛋白的单层和多层FTIR残基特异性结构研究；用俘获泡表面测定法表征这些结构体在合成表面活性剂脂质的表面活性；并采用氯/盐酸大鼠模型，评价表面活性剂失活条件下，实验表面活性剂在体内对肺功能的影响。这些研究将有助于开发用于治疗吸入有毒化学品引起的ARDS的合成表面活性剂混合物。项目描述：吸入有毒化学物质导致气道损伤、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，我们建议开发新的抗抑制和氧化应激的合成表面活性剂，并在暴露于氯气或盐酸后危及生命的呼吸系统疾病的大鼠身上进行试验。

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.