STRUCTURE AND FUNCTION OF SURFACTANT APOPROTEINS

为了实现最佳的气体交换，肺泡必须在整个呼吸周期中保持充气状态。为此，必须通过功能性表面活性剂的存在来减少作用在肺泡腔中的空气-水界面处的强表面力。 由于呼吸需求随着活动水平和疾病状态的变化而在很大范围内快速变化，因此表面活性剂系统必须能够通过调整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个级别的调节之下，因此包含编码调节信号并对其做出反应的分子（通常是蛋白质配体和受体）以及主要改变表面张力的分子（通常是两亲性分子，例如磷脂）。我们的总体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。我们将测试以下一般假设：特定表面活性剂脱辅基蛋白决定表面活性剂形式的结构，并且对于调节肺泡衬里细胞和肺泡腔之间表面活性剂的双向流动非常重要。上一次拨款期间提出的两个新观察结果对当前提案很重要。首先，我们的结果表明 SP-B 的融合活性可能与层状体组装有关。这一想法得到了小鼠研究结果的支持，肺泡表面活性剂的积累表明 SP-D 在表面活性剂体内平衡中发挥着意想不到的作用。在本申请中，我们建议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，其次研究表面活性剂蛋白-D 和细胞因子在调节肺泡 II 型细胞增殖和表面活性剂周转中的作用。

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.