EXTRACELLULAR MATRIX REPAIR IN PULMONARY EMPHYSEMA

慢性吸入香烟烟雾导致肺内 炎症细胞的募集和激活， 弹性蛋白酶，超过抑制剂。弹性纤维退化耦合 异常修复导致无序和非功能性弹性 纤维导致远端的空气空间永久性扩大， 终末细支气管，伴随着其壁的破坏， 定义为肺气肿。弹性纤维组装复杂， 将弹性蛋白原单体排列在可能的几种支架上， 微原纤维蛋白，然后通过赖氨酰交联 氧化酶以形成不溶性弹性蛋白。我们认为， 弹性蛋白原在空间和时间上协调表达， 微纤维蛋白和赖氨酰氧化酶在成年吸烟者中的作用 在肺气肿的发展中起着关键作用。有趣的是，马萨罗 等人最近已经表明，弹性蛋白酶- 诱导的肺气肿可以通过用视黄酸（RA）治疗来逆转。 虽然没有直接调查，但他们认为， 结构异常也恢复了正常的肺弹性。是 已知RA诱导成纤维细胞合成弹性蛋白原，但 这是否发生在体内和其他弹性纤维的命运 成分不明。除了弹性蛋白在肺中的重要性外， 修复，弹性蛋白可能参与永久性肺损伤， 肺气肿细胞外基质（ECM）通过以下方式提供重要信号： 这些细胞感受到它们的外部环境， 导致多种细胞反应。沿着这个主题，我们有 发现弹性蛋白的蛋白水解片段都吸引巨噬细胞， 肺和诱导巨噬细胞生物合成特异性基质 金属蛋白酶（MMPs）;巨噬细胞弹性蛋白酶和胶原酶。的 这项提案的长期目标是检验RA的假设， 在我们的小鼠香烟模型中逆转了空域扩大， 诱发的肺气肿，并确定弹性纤维在这两个作用 永久性肺泡损伤和启动肺泡修复， 肺气肿 为了实现这些目标，我们建议1。评估RA的能力， 逆转香烟烟雾诱导的成年小鼠肺气肿。2.确定 因此，弹性蛋白片段诱导MMP表达机制 永久破坏和抑制肺泡形成。3.探讨 弹性纤维修复通过a）定义空间和时间表达 弹性蛋白、微纤维蛋白和赖氨酰氧化酶在肺 发展，在响应香烟烟雾暴露，并在治疗后， 和B）定义个体免疫缺陷小鼠的能力， 弹性纤维成分，以响应肺气肿 香烟烟雾。

Chronic inhalation of cigarette smoke leads to intrapulmonary recruitment and activation of inflammatory cells with release of elastases, in excess of inhibitors. Elastic fiber degradation coupled with abnormal repair leads to disordered and non-functional elastic fibers resulting in permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls which defines emphysema. Elastic fiber assembly is complex requiring tropoelastin monomers to be aligned on a scaffold of potentially several microfibril proteins where they are then cross-linked by lysyl oxidase(s) to form insoluble elastin. We believe that inability to spatially and temporally coordinate expression of tropoelastin, microfibril proteins, and lysyl oxidase in adult cigarette smokers plays a key role in the development of emphysema. Interestingly, Massaro et.al. recently has shown that airspace enlargement following elastase- induced emphysema can be reversed by treatment with retinoic acid (RA). Although not directly investigated, they believe that correction of the structural abnormality also restored normal lung elasticity. It is known that RA induces synthesis of tropoelastin by fibroblast, but whether this occurs in vivo and the fate of other elastic fiber components is unknown. In addition to the importance of elastin in lung repair, elastin may be involved in perpetuation lung injury in emphysema. Extracellular matrix (ECM) provides important signals by which cells sense their external environment and disruption of ECM often leads to a variety of cellular responses. Along this theme, we have found that proteolytic fragments to elastin both attract macrophage to the lung and induce macrophage biosynthesis of specific matrix metalloproteinases (MMPs); macrophage elastase and collagenase . The long-term goals of this proposal are to test the hypothesis that RA reverses airspace enlargement in our murine model of cigarette smoke- induced emphysema and to define the role of elastic fibers in both perpetuating alveolar injury and in initiating alveolar repair in emphysema. To achieve these goals we propose to 1. Assess the capacity of RA to reverse cigarette smoke-induced emphysema in adult mice. 2. Determine the mechanism by which elastin fragments induce MMP expression thus perpetuating destruction and inhibiting alveolarization. 3. Investigate elastic fiber repair by a) defining the spatial and temporal expression of elastin, microfibril proteins, and lysyl oxidases during lung development, in response to cigarette smoke exposure, and upon treatment with RA, and b) defining the capacity of mice deficient in individual elastic fiber components, to develop pulmonary emphysema in response to cigarette smoke.