SP-D in pulmonary remodeling

(申请人摘要)本申请将决定肺组织的作用 肺表面活性蛋白D(SP-D)在肺部炎症和炎症反应中的调节作用 维持出生后肺泡结构。SP-D是 凝集素家族的宿主防御分子，在各种组织中表达，但 在肺中的最高水平，在先天免疫中发挥作用。SP-D 结合各种致病微生物，增强吞噬功能，调节 发炎。最近，检测到SP-D水平降低或缺失。 来自CF和RSV肺炎患者的BALF提供了一个强有力的推断 SP-D降低可能是肺部炎症的原因之一。调查人员 新近研制的靶向基因失活(SP-D-/-)缺失SP-D的小鼠 并显示促炎细胞因子和炎性细胞 经鼻或气管内滴入呼吸道后的内流 合胞病毒和甲型流感病毒SP-D(-/-)小鼠的发育 新生儿呼吸道合胞病毒感染后肺部炎症和肺泡扩大 在4天龄时。在没有呼吸道合胞病毒的情况下，肺发育正常，直到3 SP-D(-/-)小鼠自发发生肺损伤的周龄 炎症和肺气肿，表明SP-D的缺乏有助于 肺泡异常重塑。因此，本申请将测试 SP-D在肺调节中起关键作用的中心假说 呼吸道合胞病毒感染后的炎症与肺损伤保护 出生后发育中的肺。为了检验这一假设，目标1将 SP-D在RSV诱导的肺损伤中的调控作用 新生和出生后小鼠肺的炎症和呼吸道重塑。目标 2将决定SP-D是否调节 研究人员假设的蛋白水解酶/抗蛋白酶 SP-D(-/-)小鼠肺泡异常形成机制的实验研究 SP-D是否调节金属蛋白酶(NMP)-9、-2和-12。目标3将 确定SP-D特定结构域的突变是否导致或 改善新生大鼠肺炎症和气道重塑 与临床核心联合使用，用于患有慢性肺部疾病的婴儿。 这项SCOR项目将阐明SP-D在调节肺活量中的作用 炎症反应和肺泡重塑，并可能提供科学 支持使用SP-D治疗儿童慢性肺部疾病， 例如，支气管肺发育不良。

(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.