MECHANISMS OF SURFACTANT INHIBITION

关键的表面活性蛋白功能，如脂质混合，吸附， 与两亲结构域相关的动态压缩是 可能受表面活性剂抑制剂影响最大。基于已知的 表面活性蛋白SP-A、SP-B和SP-C的氨基酸序列，我们 将合成一个肽家族，用于表征 合成表面活性剂分散体与表面活性剂的相互作用 抑制剂的这些肽将包括长度短的功能结构域 （例如：SP-A、SP-B、SP-C和 代表SP-B（78个残基）和SP-C（35个残基）的全长蛋白质 残基）。评价血清成分的抑制作用， 作为血清白蛋白和抗表面活性蛋白抗体，合成的 将测试肽的体外表面活性， 没有抑制剂。还将研究表面活性剂抑制剂， 它们对表面活性剂分散体的混合功能的影响， 荧光囊泡测定。这些研究将使我们能够更好地 了解哪些表面活性蛋白起作用（即，吸附， 扩展、动态压缩和再扩展、脂质混合）是 受到抑制剂的干扰从这些体外实验中得到的信息 表面活性剂抑制试验，我们将评估 表面活性剂肽和抑制剂， 例如圆二色性（CD）、傅立叶变换红外（FTIR） 电子自旋共振（ESR）光谱，以评估蛋白质是否 抑制剂（例如，白蛋白、抗表面活性蛋白抗体）阻断 表面活性剂活性通过与两亲性的、表面寻求的 表面活性蛋白的结构域。最后，综合效益 肽-脂质混合物，有和没有抑制剂蛋白，在恢复 肺功能将在两种表面活性剂的动物模型中测试 缺陷和失活。这些实验应该能提供信息 合成表面活性剂制剂的剂量-反应关系 体内，并确定那些条件下，在体外发现的 抑制剂研究预测了合成的 表面活性剂这些信息不仅有助于确定 表面活性剂分散体的一种或多种组分抗抑制剂，而且 设计具有抗抑制性的合成表面活性剂 呼吸窘迫综合征的症状

Key surfactant protein functions, such as lipid mixing, adsorption, and dynamic compression, that are associated with amphipathic domains are probably the most affected by surfactant inhibitors. Based on the known amino acid sequences of the surfactant proteins SP-A, SP-B, and SP-C, we will synthesize a family of peptides for use in characterizing the interactions of synthetic surfactant dispersions with surfactant inhibitors. These peptides will include short length, functional domains (eg. amphipathic and transmembrane sequences) of SP-A, SP-B, SP-C and full-length proteins representing SP-B (78 residues) and SP-C (35 residues). To evaluate the inhibitory actions of serum components such as serum albumin and anti-surfactant protein antibodies, synthetic peptides will be tested for their in vitro surface activity with and without inhibitors. Surfactant inhibitors will also be investigated for their effects on the mixing function of the surfactant dispersions using fluorescence vesicle assays. These studies will allow a better understanding of which surfactant protein functions (i.e., adsorption, spreading, dynamic compression and respreading, lipid mixing) are perturbed by inhibitors. With the information derived from these in vitro tests of surfactant inhibition, we will assess the interactions between surfactant peptides and inhibitors using physical-biochemical techniques, such as circular dichroism (CD), Fourier transform infrared (FTIR) and electron spin resonance (ESR) spectroscopy, to evaluate whether protein inhibitors (e.g., albumin, anti-surfactant protein antibodies) block surfactant activity by interacting with the amphipathic, surface-seeking domains of surfactant proteins. Finally, the effectiveness of synthetic peptide-lipid mixtures, with and without inhibitor proteins, in restoring lung function will be tested in two animal models of surfactant deficiency and inactivation. These experiments should provide information on dose-response relationships of synthetic surfactant preparations in vivo and identify those conditions under which the in vitro findings of the inhibitor studies predict the in vivo function of synthetic surfactants. This information may not only help in determining component(s) of a surfactant dispersion resist inhibitors, but also in designing synthetic surfactants that offer resistance against inhibition in the respiratory distress syndrome.