ROLE OF SURFACTANT PROTEIN B IN INNATE AIRWAY DEFENSE

表面活性蛋白 B 在先天气道防御中的作用

• 批准号: 6537911
• 负责人: JOHN E BAATZ
• 金额: $ 28.11万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537911
• 关键词: antibacterial agents; bacterial disease; biopsy; biotechnology; biotherapeutic agent; cystic fibrosis; drug design /synthesis /production; enzyme linked immunosorbent assay; gene expression; gene targeting; genetically modified animals; host organism interaction; human subject; immunocytochemistry; laboratory mouse; lung lavage; mucosal immunity; patient oriented research; protein localization; protein structure function; proteolipids; pulmonary surfactants; respiratory infections; tissue /cell culture; western blottings

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.

描述（申请人的摘要）：表面活性剂蛋白B（SP-B）是必不可少的 用于产后存活和正常表面活性剂功能。 SP-B有能力 重组脂质双层，是熔融蛋白。基于这些 SP-B的氨基酸序列的特征和相似性与 几种抗菌肽，我们假设SP-B本身具有 抗菌特性。我们实验室获得的初步数据 证明他的SP-B具有体外抗菌活性。的意义 这个观察结果是三个方面。第一个SP-B仅在哺乳动物中表达 肺部被支气管分泌到气道衬里的地方， 支气管和肺泡上皮细胞以相对较高的浓度。 因此，它可以作为局部粘膜免疫的组成部分，以防止 这些肺部和其他区域中的细菌感染。其次，表面活性剂 目前使用含有SP-B的替换制剂用于安全治疗 新生儿呼吸窘迫综合征，此类制剂不会引起 免疫反应。第三，SP-B很容易隔离或合成。因此， 有可能安全使用SP-B治疗肺部 细菌感染。使用SP-B预防或消除细菌的生长 气道在囊性纤维化（CF）中特别重要，其中 持续的细菌感染会导致进行性肺损伤。 此外，我们在支气管肺泡灌洗中发现了异常形式的SP-B形式（BAL） 成人CF患者和成熟的SP-B可能会降解或修饰。我们将 测试SP-B是先天肺免疫的组成部分的假设 系统，保护人类气道免受细菌感染的影响，这 在CF患者的气道中，活动可能会受到损害。这个目的 提案是1）确定BAL中SP-B的分子形式和活性 CF患者与正常人的患者，2）描绘气道中的位置 在发现SP-B的地方可以发挥防御作用，3） 表征体外SP-B的抗菌活性，以及​​4） 包含本机或合成SP-B的制剂用作抗菌 体内代理。提议的实验的结果将奠定基础 用于消除细菌肺部感染的SP-B治疗用途。