SYNDECANS IN MODELS OF BRONCHOPULMONARY DYSPLASIA

新生儿BPD发病机制的一个主要方面是对高FiO 2下机械通气引起的损伤的炎症反应。通气胎狒狒发展的病理生理学，组织学和生物化学特征的婴儿与BPD，并提供了一个机会，以测试假设的发病机制BPD和评估预防和治疗措施。我们研究了细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）被称为syndecans。这些单跨膜蛋白含有细胞外结构域（胞外域），其在远离质膜的N-末端附近携带HS链。多配体聚糖位于每个粘附细胞的表面上，在那里它们充当多种生长因子、细胞因子、趋化因子和细胞粘附分子的共受体，以及部分地协调对组织损伤的高度复杂的修复反应。具体地，多配体蛋白聚糖-1和-4响应于组织损伤而被诱导，在组织损伤期间产生的试剂导致多配体蛋白聚糖胞外域从细胞表面完整释放，产生可溶性效应物，其改变多种蛋白质的活性并充当显性负抑制剂。含有syndecan-1基因的靶向缺失的小鼠和在广泛作用的CMV启动子下转基因过表达syndecan-1的小鼠在伤口修复中显示出重大缺陷：无效小鼠显示出对损伤的缓慢上皮反应，而过表达小鼠脱落过量的可溶性syndecan-1胞外域，导致损伤修复中的重大干扰。我们假设，在高FiO 2下机械通气对肺的持续性损伤导致可溶性多配体蛋白聚糖胞外域的过度脱落，这些PG的生物活性延迟了修复反应，并导致病理学和临床上公认为BPD的变化，降低这些胞外域的水平将部分改善BPD的进展。具体而言，我们的目标是（i）将多配体蛋白聚糖表达和脱落与通气早产狒狒肺的组织病理学变化相关联;（ii）确定通气肺中可溶性胞外域的生物活性;（iii）建立狒狒肺培养物以研究多配体蛋白聚糖诱导和脱落的机制并产生多配体蛋白聚糖胞外域;（iv）评估可溶性胞外域是否与狒狒模型中BPD的发展偶然相关。

A major aspect of the pathogenesis of BPD in newborns is the inflammatory response to injury caused by mechanical ventilation at high FiO2. Ventilated fetal baboons develop the pathophysiological, histologic and biochemical features of the infant with BPD, and provide an opportunity to test hypothesis for the pathogenesis of BPD and to evaluate preventative and therapeutic measures. We study the cell surface heparan sulfate proteoglycans (HSPGs) known as the syndecans. These single membrane spanning protein contain extracellular domains (ectodomains) that bear HS chains near the N- termini, distant from the plasma membrane. Syndecans are on the surface of every adherent cell where they act as co-receptors for a variety of growth factors, cytokines, chemokines and cell adhesion molecules, as well as coordinate, in part, the highly complex reparative response to tissue injury. Specifically, syndecan-1 and -4 are induced in response to tissue injury, agents produced during tissue injury cause syndecan ectodomains to be released intact from cell surfaces, yielding soluble effectors that modify the activities of wide variety of proteins and act as dominant negative inhibitors. Mice containing a targeted deletion of the syndecan-1 gene and mice that transgenically over-express syndecan-1 under the broadly acting CMV promoter show major defects in wound repair: the null mice show slow epithelial response to injury and the over-expressing mice shed excessive amounts of the soluble syndecan-1 ectodomains, causing a major disturbance in repair of injury. We hypothesize that the persistent injury of the lung by mechanical ventilation at high FiO2 leads to excessive shedding of the soluble syndecan ectodomains, that the biological activities of these PGs delay the reparative response and contribute to the changes recognized pathologically and clinically as BPD, and reducing the level of these ectodomains will ameliorate, in part, the progression to BPD. Specifically, we aim to (i) to correlate syndecan expression and shedding with histopathological changes in ventilated pre-term baboon lungs; (ii) determine the biological activities of the soluble ectodomains from ventilated lungs; (iii) establish baboon lung cultures to investigate mechanisms of syndecan induction and shedding and to produce syndecan ectodomains; (iv) assess whether the soluble ectodomains are casually related to development of BPD in the baboon models.