Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide.
Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide.
复制标题
新型合成肺表面活性剂的活性和生物物理抑制抗性，该肺表面活性剂含有超微米-B Datk肽。
作者：
Notter RH;Wang Z;Walther FJ
背景/目标。本研究检测了含有甘油磷脂的合成肺表面活性剂与Super Mini-B（S-MB）DATK（肺表面活性蛋白（SP）-B的新型稳定分子模拟物）联合的表面活性、对生物物理抑制的抗性和肺部疗效。这项工作的目的是测试S-MB DATK合成表面活性剂是否具有良好的生物物理和生理活性，用于未来治疗肺疾病或损伤中的表面活性剂缺乏或功能障碍。方法.通过同源模建和FTIR光谱分析S-MB DATK肽的结构。在存在和不存在白蛋白、溶血磷脂酰胆碱（lyso-PC）和游离脂肪酸（棕榈油酸和油酸）的情况下，评估合成S-MB DATK表面活性剂的体外表面活性和抗抑制性。吸附和动态表面张力降低用搅拌亚相皿装置和脉动气泡表面计（20个循环/分钟，50%面积压缩，37 °C）测量。在具有表面活性剂缺乏/功能障碍的通气兔中测量S-MB DATK表面活性剂的体内肺活性，所述表面活性剂缺乏/功能障碍由导致动脉PO 2值<100 mmHg的重复肺灌洗诱导。结果在所有评估中，S-MB DATK表面活性剂具有非常高的表面活性。该制剂在37 °C下快速吸附至46-48 mN/m的表面压力（22-24 mN/m的低平衡表面张力），并且在脉动气泡表面张力计上的动态压缩下将表面张力降低至<lmN/m。S-MB DATK表面活性剂显示出显著的抵抗血清白蛋白、C16：0溶血-PC和游离脂肪酸抑制的能力，但表面活性剂抑制通过增加表面活性剂浓度而减轻。S-MB DATK合成表面活性剂对严重表面活性剂缺乏的机械通气兔气管内滴注后迅速改善动脉氧合和肺顺应性。结论. S-MB DATK是天然SP-B的活性模拟物。含有S-MB DATK（或相关肽）与脂质组合的合成表面活性剂似乎具有治疗表面活性剂缺乏或功能障碍的临床状态（例如新生儿和急性呼吸窘迫综合征）的显著未来潜力。
Background/objectives. This study examines the surface activity, resistance to biophysical inhibition, and pulmonary efficacy of a synthetic lung surfactant containing glycerophospholipids combined with Super Mini-B (S-MB) DATK, a novel and stable molecular mimic of lung surfactant protein (SP)-B. The objective of the work is to test whether S-MB DATK synthetic surfactant has favorable biophysical and physiological activity for future use in treating surfactant deficiency or dysfunction in lung disease or injury. Methods. The structure of S-MB DATK peptide was analyzed by homology modeling and by FTIR spectroscopy. The in vitro surface activity and inhibition resistance of synthetic S-MB DATK surfactant was assessed in the presence and absence of albumin, lysophosphatidylcholine (lyso-PC), and free fatty acids (palmitoleic and oleic acid). Adsorption and dynamic surface tension lowering were measured with a stirred subphase dish apparatus and a pulsating bubble surfactometer (20 cycles/min, 50% area compression, 37 °C). In vivo pulmonary activity of S-MB DATK surfactant was measured in ventilated rabbits with surfactant deficiency/dysfunction induced by repeated lung lavages that resulted in arterial PO2 values <100 mmHg. Results. S-MB DATK surfactant had very high surface activity in all assessments. The preparation adsorbed rapidly to surface pressures of 46–48 mN/m at 37 °C (low equilibrium surface tensions of 22–24 mN/m), and reduced surface tension to <1 mN/m under dynamic compression on the pulsating bubble surfactometer. S-MB DATK surfactant showed a significant ability to resist inhibition by serum albumin, C16:0 lyso-PC, and free fatty acids, but surfactant inhibition was mitigated by increasing surfactant concentration. S-MB DATK synthetic surfactant quickly improved arterial oxygenation and lung compliance after intratracheal instillation to ventilated rabbits with severe surfactant deficiency. Conclusions. S-MB DATK is an active mimic of native SP-B. Synthetic surfactants containing S-MB DATK (or related peptides) combined with lipids appear to have significant future potential for treating clinical states of surfactant deficiency or dysfunction, such as neonatal and acute respiratory distress syndromes.