SP-D in pulmonary remodeling

SP-D 在肺重构中的作用

• 批准号: 6644992
• 负责人: Thomas R Korfhagen
• 金额: $ 22万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6644992
• 关键词: clinical research; disease /disorder proneness /risk; human tissue; immunomodulators; inflammation; laboratory mouse; lung development; lung injury; mammalian embryology; metalloendopeptidases; molecular pathology; newborn animals; protein structure function; pulmonary surfactants; respiratory epithelium; respiratory infections; respiratory syncytial virus; tissue inhibitor of metalloproteinases

(Applicant's Abstract) This application will determine the role of pulmonary surfactant protein D (SP-D) in the modulation of pulmonary inflammation and maintenance of postnatal alveolar structure. SP-D is a member of the collectin family of host defense molecules expressed in various tissues, but at highest levels in the lung where it plays a role in innate immunity. SP-D binds various pathogenic microbes, enhancing phagocytosis, and modulating inflammation. Recently, decreased or absent levels of SP-D were detected in BALF from patients with CF and RSV pneumonia providing a strong inference that decreased SP-D may contribute to lung inflammation. The investigators recently developed mice lacking SP-D by targeted gene inactivation (SP-D -/-) and demonstrated increased pro-inflammatory cytokines and inflammatory cell influx following intranasal or intratracheal instillation of respiratory syncytial virus (RSV) and influenza virus A. SP-D (-/-) mice developed pulmonary inflammation and enlarged alveoli following neonatal RSV infection at 4 days of age. In the absence of RSV, lung development was normal, until 3 weeks of age when SP-D (-/-) mice spontaneously developed pulmonary inflammation and emphysema, demonstrating that lack of SP-D contributes to abnormal alveolar remodeling. Thus, the present application will test the central hypothesis that SP-D plays a critical role in modulation of lung inflammation and protection against pulmonary injury following RSV infection of the postnatal developing lung. To test the hypothesis, Aim 1 will determine the role of SP-D in the modulation of RSV induced pulmonary inflammation and airway remodeling in neonatal and postnatal mouse lungs. Aim 2 will determine whether SP-D regulates the balance of proteinases/antiproteinases that the investigators hypothesize underlies the pathogenesis of abnormal alveolar formation in the SP-D (-/-) mice by testing whether SP-D regulates metalloproteinases (NMP) -9, -2, and -12. Aim 3 will determine whether mutations in specific domains of SP-D contribute to or ameliorate neonatal lung inflammation and airway remodeling in mice or in conjunction with the Clinical Core, in infants with chronic lung disease. This SCOR project will clarify the role of SP-D in modulating pulmonary inflammatory responses and alveolar remodeling and may provide scientific support for the use of SP-D in treatment of chronic lung diseases of children, e.g. bronchopulmonary dysplasia.

（申请人摘要）该应用将确定肺的作用 表面活性蛋白D（SP-D）在调节肺部炎症和 维持出生后的肺泡结构。SP-D是 凝集素家族的宿主防御分子在各种组织中表达，但 在肺中含量最高，在先天免疫中发挥作用。SP-D 结合各种病原微生物，增强吞噬作用，并调节 炎症最近，检测到SP-D水平降低或缺失， CF和RSV肺炎患者的BALF提供了强有力的推论， 降低的SP-D可能导致肺部炎症。调查人员 最近开发的小鼠缺乏SP-D通过靶向基因失活（SP-D -/-） 并显示促炎细胞因子和炎性细胞增加 鼻内或鼻腔内滴注呼吸道 合胞病毒（RSV）和流感病毒A。SP-D（-/-）小鼠 新生儿呼吸道合胞病毒感染后肺部炎症和肺泡扩大 在4天的年龄。在没有RSV的情况下，肺发育正常，直到3 当SP-D（-/-）小鼠自发地发生肺 炎症和肺气肿，表明缺乏SP-D有助于 异常肺泡重塑因此，本申请将测试本发明。 SP-D在肺的调节中起关键作用的中心假设 呼吸道合胞病毒感染后炎症和肺损伤保护 出生后发育中的肺为了检验这一假设，目标1将 确定SP-D在RSV诱导的肺细胞凋亡中的作用。 新生和出生后小鼠肺的炎症和气道重塑。目的 2将决定SP-D是否调节 研究人员假设这些蛋白酶/抗蛋白酶是 SP-D（-/-）小鼠肺泡形成异常的发病机制 SP-D是否调节金属蛋白酶（NMP）-9、-2和-12。目标3将 确定SP-D特定结构域中的突变是否有助于或 改善小鼠或小鼠的新生儿肺部炎症和气道重塑。 与临床核心，在婴儿慢性肺部疾病。 该SCOR项目将阐明SP-D在调节肺动脉高压中的作用。 炎症反应和肺泡重塑，并可能提供科学的 支持使用SP-D治疗儿童慢性肺病， 例如支气管肺发育不良