INTERFACIAL ADSORPTION OF PULMONARY SURFACTANT

这一建议将确定肺表面活性剂吸附到空气-水界面的机制。表面活性剂是脂质和蛋白质的混合物，覆盖在肺泡边缘的薄液体层上。表面活性剂的薄膜降低了空气-水界面的表面张力，使小空气空间的崩塌最小化。出生时缺乏足够表面活性剂水平的早产儿经常死于呼吸衰竭，除非用外源性表面活性剂治疗。表面活性剂异常的成人也可以从治疗性表面活性剂中获益，但目前最有效的药物缺乏足够的量。了解天然表面活性剂的活性可以指导开发廉价的人工活性剂。为了有效地发挥作用，肺表面活性剂必须迅速吸附到空气-水界面。表面活性剂制剂在界面上人工扩散时效果良好，但如果它们吸附缓慢，则在肺中无效。我们之前的结果表明，吸附发生在一系列可区分的步骤中，包括最初的囊泡与界面并置，随后的囊泡插入界面，以及后期的吸附加速，在此期间，表面活性剂以某种方式相互作用以产生更快的速率。我们的数据表明，插入界面是通过囊泡和界面之间的紧密弯曲结构发生的，并且吸附的热力学障碍是由紧密弯曲的脂质片中酰基链的分离引起的不利焓。具体的目标将检验直接遵循这个一般模型的假设。我们将比较不同表面活性剂组分和外部因素在吸附的不同阶段的影响，以及在囊泡或预先存在的单层中对吸附的动力学和热力学屏障组分的影响，以确定它们是否通过相同或不同的机制起作用。我们将使用布鲁斯特角度显微镜监测界面附近未吸附的物质，并使用荧光显微镜跟踪吸附膜的组成。

This proposal will determine the mechanisms by which pulmonary surfactant adsorbs to an air-water interface. Surfactant is the mix of lipids and proteins that coat the thin liquid layer which lines the alveoli. The thin film of surfactant lowers the surface tension of the air-water interface and minimizes collapse of the small air spaces. Premature babies born without adequate levels of surfactant frequently die from respiratory failure unless treated with exogenous surfactant. Adults with abnormal surfactant might also benefit from therapeutic surfactant, but the most effective agents currently are unavailable in sufficient quantities. Understanding the activity of native surfactant may direct efforts to develop inexpensive artificial agents. To function effectively, pulmonary surfactant must adsorb rapidly to the air-water interface. Surfactant preparations that function well when spread artificially at an interface are ineffective in the lung if they adsorb slowly. Our previous results suggest that adsorption occurs in a series of distinguishable steps that include the initial juxtaposition of vesicles to the interface, the subsequent insertion of vesicles into the interface, and a late acceleration of adsorption during which surfactant somehow interacts cooperatively to produce faster rates. Our data suggest that insertion into the interface occurs via a tightly curved structure intermediate between the vesicle and the interface, and that the thermodynamic barrier to adsorption is the unfavorable enthalpy caused by the separation of acyl chains in the tightly bent lipid lamellae. The specific aims will test hypotheses that follow directly from this general model. We will compare the effect of different surfactant components and of extrinsic factors at different stages of adsorption and in the vesicles or in preexisting monolayers on the kinetics and the components of the thermodynamic barrier to adsorption to determine if they function by the same or different mechanisms. We will use Brewster angle microscopy to monitor unadsorbed material adjacent to the interface and fluorescence microscopy to follow the composition of the adsorbed film.