STRUCTURE AND FUNCTION OF SURFACTANT APOPROTEINS

为了获得最佳的气体交换，肺泡必须在整个呼吸循环中保持充气状态。为了实现这一点，必须通过功能性表面活性剂的存在来降低作用于肺泡腔内空气-水界面的强表面力。由于呼吸需求在很大范围内随着活动水平的变化和疾病状态的变化而迅速变化，表面活性剂系统必须能够通过调节肺泡水平的分泌和清除率来快速响应这种变化。这一切都意味着表面活性剂系统必须处于多层调控之下，因此包含编码调控信号并对其作出反应的分子（典型的蛋白质配体和受体）以及主要改变表面张力的分子（典型的两亲分子，如磷脂）。我们的广泛目标是有助于详细了解表面活性剂代谢的分子控制以及它们在疾病状态下如何改变。我们将验证表面活性剂载脂蛋白决定表面活性剂形式结构的一般假设，并在调节表面活性剂在肺泡衬细胞和肺泡腔之间的双向通量中发挥重要作用。在上一个赠款期间提出的两项新意见对目前的建议很重要。首先，我们的研究结果表明SP-B的促聚变活性可能与层状体组装有关。这一观点得到了小鼠实验结果的支持，肺泡表面活性剂的积累表明SP-D在表面活性剂稳态中起着意想不到的作用。在本研究中，我们拟研究表面活性剂蛋白- b可能与板层体组装相关的分子作用，其次，表面活性剂蛋白- d和细胞因子在肺泡II型细胞增殖和表面活性剂转换调节中的作用。

For optimal gas exchange the pulmonary alveolus must remain in an inflated state throughout the respiratory cycle. For this to occur the strong surface forces acting at the air-water interface in the alveolar lumen must be reduced by the presence of a functional surfactant. Because respiratory demands vary rapidly over a wide range with changing levels of activity and in disease states, the surfactant system must be capable of quickly responding to such changes with adjustments in rates of secretion and clearance at the alveolar level. This all implies the surfactant system must be under multiple levels of regulation and therefore contain molecules that both encode regulatory signals and respond to them (typically protein ligands and receptors) as well as molecules which primarily alter surface tension (typically amphipathic molecules such as phospholipids). Our broad objective is to contribute to a detailed understanding of the molecular controls of surfactant metabolism and how they may be altered in disease states. We will test the general hypothesis that specific surfactant apoproteins determine the structure of surfactant forms and are important in regulating the bi-directional flux of surfactant between alveolar lining cells and the alveolar lumen. Two novel observations made during the last grant period are important to the current proposal. First, our results suggested the fusogenic activity of SP-B may be relevant to lamellar body assembly. This idea is supported by findings in mice and accumulation of alveolar surfactant suggested an unsuspected role for SP-D in surfactant homeostasis. In this application we propose to study the molecular actions of surfactant protein-B that might be relevant to lamellar body assembly, and second, the role(s) of surfactant protein-D and cytokines in the regulation of alveolar type II cell proliferation and surfactant turnover.