Syndecans: modulators of lung inflammation

(申请人摘要)体重1000克的婴儿出现的“新BPD”是 以假设由损伤引起的病理变化为特征的 导致炎症和增加感染易感性的肺部疾病。 这些反过来又被认为是为了中断肺部发育，尤其是 延缓肺泡化和血管生成。其后果是肺性的 功能不全，导致氧合困难和易患 医院感染。这种BPD很难预防或治疗， 矛盾的是，它的发病率正在增加，因为 这些婴儿。 最近的证据表明，Syndecans，高度丰富的细胞表面 硫酸乙酰肝素蛋白多糖(HSPGs)，调节炎症和宿主防御。 这些跨膜蛋白具有胞外区(胞外区)， 在N-末端附近有HS链，远离质膜。 Syndecans存在于每个贴壁细胞的表面，由于 它们的HS链对蛋白质的高亲和力，它们充当 参与损伤修复和宿主防御的分子。Syndecan-1和-4 是在肺部对高氧的反应而诱导的，而在 组织损伤导致其胞外区域脱落到炎性液体中 (皮肤伤口液，呼吸机婴儿和狒狒的气管抽吸物) 在那里它们可以改变生长因子和蛋白质分解平衡。两个Syndecan-1 转基因过表达syndecan-1的空白小鼠和广泛 代理启动子显示伤口修复有缺陷；无效小鼠在 上皮复极化与过度表达的小鼠过度脱落 Syndecan-1胞外结构域，改变细胞增殖和蛋白分解 伤口有活动。一种已知的铜绿假单胞菌毒力因子 加速Syndecan-1在肺内的脱落，其中胞外结构域增强了 微生物？S的毒力，推测是通过干扰寄主防御。 这项拨款旨在检验这样一种假设，即过度脱发 Syndecan胞外结构域在BPD的发病机制中起着重要作用，在此之前 提供新的预防和/或方法的不受重视的角色 治疗性干预。为了探索这一假说，研究人员的目标是 为了i)使用转基因和空小鼠来建立对 Syndecans在小鼠肺损伤反应中的作用；ii)确定 Syndecan-1和-4在肺反应中的诱导和脱落机制 损伤；iii)评估Syndecan胞外结构域脱落的后果 肺部炎症与宿主防御；iv)与临床结果相关 早产呼吸机婴儿的气管吸气水平和活动度 Syndecan-1和-4胞外区。

(Applicant's Abstract) The "new BPD" seen in infants of < 1000g is characterized by pathologic changes hypothesized to arise from injury to the lung that lead to inflammation and increased susceptibility to infection. These in turn are proposed to interrupt pulmonary development, especially retarding alveolarization and angiogenesis. The consequence is pulmonary insufficiency, resulting in difficult oxygenation and susceptibility to nosocomial infection. This BPD is difficult to prevent or treat and, paradoxically, its incidence is increasing because of improved survival of these infants. Recent evidence indicates that the syndecans, highly abundant cell surface heparan sulfate proteoglycans (HSPGs), modulate inflammation and host defense. These transmembrane proteins have extracellular domains (ectodomains) that bear HS chains near their N-termini, distant from the plasma membrane. Syndecans are on the surface of every adherent cell where, by virtue of the high affinity of their HS chains for proteins, they act as co-receptors for molecules involved in the repair of injury and host defense. Syndecan-1 and -4 are induced in the lung in response to hyperoxia, and agents produced during tissue injury cause their ectodomains to be shed into inflammatory fluids (skin wound fluids, tracheal aspirates from ventilated infants and baboons) where they can modify growth factor and proteolytic balance. Both syndecan-1 null mice and mice that transgenically overexpress syndecan-1 under a broadly acting promotor show defective wound repair; the null mice are impaired in epithelial repolarization and the overexpressing mice excessively shed syndecan-1 ectodomains, which alter cell proliferation and proteolytic activity in the wound. A known Pseudomonas aeruginosa virulence factor accelerates syndecan-1 shedding in the lung where the ectodomain enhances the microbe?s virulence, presumably by interfering with host defenses. This grant is designed to test the hypothesis that excessive shedding of syndecan ectodomains contributes to the pathogenesis of BPD, a previously unappreciated role that provides new approaches to preventive and/or therapeutic interventions. To explore this hypothesis, the investigators aim to i) use transgenic and null mice to establish the regulatory role of syndecans in the response to lung injury in the mouse; ii) determine the mechanisms of syndecan-1 and -4 induction and shedding in response to lung injury; iii) Evaluate consequences of syndecan ectodomain shedding for pulmonary inflammation and host defense; iv) correlate clinical outcomes of pre-term ventilated infants with their tracheal aspirate levels and activities of syndecan-1 and -4 ectodomains.