Synthetic surfactant and toxic chemical lung injury

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。虽然这些影响是众所周知的，但缺乏特定的解毒剂限制了先前治疗干预的有效性。由于表面活性物质的失活和自由基的形成是急性肺损伤和水肿的重要途径，我们建议在暴露于剧毒化学物质的大鼠中测试合成的表面活性物质。合成表面活性剂具有生产规模大、保质期长的优点，很容易被用来优化对失活的抗性。本实验室设计、合成和表征了几种高活性表面活性物质蛋白B(SP-B)和C(SP-C)模拟物(mini-B、超mini-B、maxi-B和SP-CFF)，作为目前用于新生儿呼吸窘迫综合征(RDS)的天然肺表面活性物质的合成替代品。这些合成表面活性蛋白模拟物是在人工肺灌洗脂类和抗磷脂酶磷脂酰胆碱(如DEPN-8)中合成的，目前正在研究其在急性RDS(ARDS)中的有效性，ARDS具有吸入剧毒化学品继发肺损伤的许多特征。本应用的具体目的是：i)合成和表征新型合成表面活性剂模拟蛋白质和抗磷脂酶磷脂，旨在具有高脂结合、表面活性和抗抑制性；以及ii)测试优化的表面活性制剂对暴露于剧毒气体(例如氯)或液体(例如盐酸)所致急性肺损伤大鼠的体内疗效。这些具体目标将通过一整套技术实现，包括合成SP-B和C的多肽结构；用2D-核磁共振技术研究SP-B和C多肽的溶液结构；研究SP-B和C多肽和蛋白质的单层和多层FTIR残基特定结构；通过捕获气泡表面检测仪表征这些结构在合成表面活性脂类中的表面活性；以及使用氯/盐酸大鼠模型来评估实验表面活性物质在活体条件下对肺功能的影响。这些研究应有助于开发用于治疗吸入有毒化学品引起的急性呼吸窘迫综合征的合成表面活性剂混合物。项目简介：吸入有毒化学物质会导致呼吸道损伤、支气管收缩和继发于表面活性物质抑制和自由基形成的严重肺水肿。外源性表面活性物质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物质，并在暴露于氯气或盐酸后威胁生命的呼吸系统疾病的大鼠身上进行测试。

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.