ROLE OF SURFACTANT PROTEIN B IN INNATE AIRWAY DEFENSE

描述(申请人摘要)：表面活性蛋白B(SP-B)是必需的 用于出生后存活和正常的表面活性物质功能。SP-B能够 重组脂双层，是一种产脂蛋白。基于这些 SP-B与SP-B的氨基酸序列特征及相似性 几种抗菌肽，我们假设SP-B本身具有 抗菌性能。我们实验室获得的初步数据 证明SP-B具有体外抗菌活性。的重要意义。 这一观察结果有三个方面。第一个SP-B仅在哺乳动物中表达 通过支气管将其分泌到呼吸道衬里液体的肺部， 较高浓度的细支气管和肺泡上皮细胞。 因此，它可以作为局部粘膜免疫的一个组成部分，以防止 肺部这些区域和其他区域的细菌感染。第二，表面活性剂 含有SP-B的替代制剂目前用于安全治疗 新生儿呼吸窘迫综合征，而这种准备不会引起 免疫反应。第三，SP-B易于分离或合成。因此， SP-B在治疗肺源性心脏病中有安全应用的潜力 细菌感染。使用SP-B预防或根除细菌生长 在囊性纤维化(CF)中，呼吸道尤其重要， 进行性肺损伤是由于持续的细菌感染造成的。 此外，我们还在支气管肺泡灌洗(BAL)中发现了SP-B的异常形式。 成熟的SP-B可能被降解或修饰。我们会 检验SP-B是先天肺免疫成分的假设 系统，保护人类呼吸道免受细菌感染，而这 CF患者的呼吸道活动可能受到影响。这样做的目的是 建议1)确定BAL中SP-B的分子形式和活性 Cf患者与正常人，2)描绘呼吸道部位 在发现SP-B并可能在其中发挥防御作用的地方，3) 鉴定SP-B的体外抗菌活性，以及4)开发 含有天然或合成SP-B的抗菌制剂 活体内的特工。拟议中的实验结果将奠定基础 用于治疗使用SP-B根除细菌性肺部感染。

DESCRIPTION (Applicant's Abstract): Surfactant protein B (SP-B) is essential for postnatal survival and normal surfactant function. SP-B is capable of reorganizing lipid bilayers and is fusigenic protein. Based on these characteristics and the similarity of SP-B's amino acid sequence to those of several antimicrobial peptides, we hypothesized that SP-B itself has antimicrobial properties. Preliminary data obtained by our laboratory have demonstrated he SP-B has in vitro antibacterial activity. The significance of this observation is three-fold. First SP-B is expressed solely in mammalian lungs where it is secreted into the airway lining fluid by bronchial, bronchiolar and alveolar epithelial cells at relatively high concentrations. For that reason, it may act as a component of local mucosal immunity to prevent bacterial infections in these and other regions of the lung. Second, surfactant replacement preparations containing SP-B are presently used for safe treatment of neonatal respiratory distress syndrome, and such preparations do not elicit immunological responses. Third, SP-B is easily isolated or synthesized. Thus, there is potential for safe therapeutic use of SP-B for treatment of pulmonary bacterial infections. Use of SP-B to prevent or eradicate bacterial growth in the airway would be of particular importance in cystic fibrosis (CF), where progressive lung damage occurs as a result of persistent bacterial infection. Moreover, we have found aberrant forms of SP-B in bronchoalveolar lavage (BAL) of adult CF patients and that mature SP-B may be degraded or modified. We will test the hypothesis that SP-B is a component of the innate pulmonary immune system, protecting the human airway against bacterial infection, and this activity may be compromised in the airways of CF patients. The aims of this proposal are 1) to determine molecular forms and activity of SP-B in BAL from CF patients vs. those of normal humans, 2) to delineate the sites in the airway where SP-B is found and in which it may play a defensive role, 3) to characterize the antibacterial activity of SP-B in vitro, and 4) to develop preparations containing native or synthetic SP-B for use as antibacterial agents in vivo. Results from the proposed experiments will lay the foundation for therapeutic use of SP-B for eradication of bacterial lung infections.