ROLE OF SURFACTANT PROTEINS IN PULMONARY HOST DEFENSE

表面活性剂是由肺泡上皮II型细胞分泌到气隙的液体衬里中的脂蛋白复合物，在气隙中表面活性剂执行两种功能。第一，表面活性剂降低空气-液体界面处的表面张力，第二，表面活性剂参与保护肺免受病原体的侵害。上一个资助期以及其他实验室的工作提供了证据，证明两种亲水性表面活性剂蛋白SP-A和SP-D调理并增强肺泡巨噬细胞对病原体的摄取。SP-A和SP-D的水平在急性肺损伤模型中增加，并且可以增加免疫细胞向感染或炎症部位的迁移。我们最近的数据表明，SP-A和SP-D也调节免疫细胞反应。如果过量会引起炎症并损伤脆弱的肺上皮。众所周知，许多免疫细胞反应是一把双刃剑：即帮助对抗入侵病原体的反应也可能伤害宿主组织。我们假设SP-A和SP-D对肺泡巨噬细胞（非炎症肺中的主要免疫细胞）和中性粒细胞（炎症肺中的主要免疫细胞）发挥选择性作用。最终结果是宿主组织得到有效保护，而不会诱导损伤性促炎反应。提出了四个目标。目的是确定SP-A和SP-D是否选择性地调节肺泡巨噬细胞和中性粒细胞产生细胞因子，从而保护宿主，但使炎症最小化。目的2是确定SP-A下调巨噬细胞产生TNF-α的机制，并确定SP-D是否通过类似的机制具有类似的作用。目的3研究SP-A和SP-D与中性粒细胞相互作用的功能意义，特别是研究SP-A和SP-D在促进凋亡中性粒细胞清除中的作用。目的4：研究SP-A和SP-D受体，包括膜结合型和可溶型的gp 340，在调节巨噬细胞功能中的作用。这些研究将有助于确定免疫细胞调节的机制，并可能对开发用于治疗成人和儿童炎症和感染性肺部疾病的新型表面活性剂疗法具有重要意义。

Surfactant is a lipoprotein complex secreted by the alveolar epithelial type II cell into the liquid lining of the airspaces where it carries out two functions. First surfactant reduces surface tension at the air-liquid interface and second, surfactant participates in protecting the lung from pathogens. Work from the previous funding period as well as from other laboratories has provided evidence that the two hydrophilic surfactant proteins, SP-A and SP-D, opsonize and enhance the uptake of pathogens by alveolar macrophages. The levels of SP-A and SP-D are increased in a model of acute lung injury and can increase the migration of immune cells to sites of infection or inflammation. Our most recent data suggest that SP-A and SP- D also modulate immune cell responses that. if excessive could cause inflammation and damage the delicate pulmonary epithelium. It is well established that many immune cell responses are a double-edged sword: i.e. the responses that help fight invading pathogens can also harm the host tissue. We hypothesize that SP-A and SP-D exert selective effects on alveolar macrophages the primary immune cell in the non-inflamed lung and on neutrophils, the primary immune cell in the inflamed lung. The net result is that host tissue is effectively defended without induction of a damaging proinflammatory response. Four aims are proposed. Aim l is to determine if SP-A and SP-D selectively modulate production of cytokines by alveolar macrophages and neutrophils so that the host is defended but inflammation is minimized. Aim 2 is to define the mechanism by which SP-A down regulates macrophage production of TNF-alpha and to determine if SP-D has similar effects via similar mechanisms. Aim 3 is to investigate the functional significance of the interaction of SP-A and SP-D with neutrophils, and, in particular, to examine the role of SP-A and SP-D in facilitating the clearance of apoptotic neutrophils. Aim 4 is to investigate the role SP-A and SP-D receptors, including a membrane bound and soluble form of gp340, in regulating macrophage function. These studies will help define mechanisms of immune cell regulation and could have important implications for developing novel surfactant therapies for treatment of inflammatory and infectious lung diseases in adults and children.