MACROPHAGE ELASTASE IN EMPHYSEMA

慢性暴露于香烟烟雾导致肺气肿 1）炎症细胞募集在终末气隙内， 肺，然后2）从肺中释放弹性蛋白酶 炎症细胞，加上3）弹性纤维的不适当修复 可能还有其他细胞外基质成分。在原 建议，我们研究了巨噬细胞弹性蛋白酶（ME）的作用， 金属蛋白酶的克隆和特点，在我们的实验室， 肺气肿的发展。我们发现人类ME能够 降解许多细胞外基质蛋白，包括弹性蛋白， 它的表达在吸烟者的巨噬细胞中被诱导， 肺气肿患者。直接确定的贡献 通过基因靶向的巨噬细胞弹性蛋白酶缺陷（MME-/-）小鼠，和3） 对MME-/-小鼠和野生型（MM+/+）同窝小鼠进行慢性 香烟烟雾暴露。我们发现，与MME+/+小鼠相比， 缺乏MME（MME-/-）的患者不发生肺气肿。令人惊讶的是，MME-/-小鼠 也未能招募巨噬细胞进入他们的肺部， 香烟烟雾。这些发现表明MME在 小鼠吸烟相关肺气肿的发病机制并导致 肺气肿的三个主要方面的假说。1)[炎症 定义蛋白酶在单核细胞募集中的作用 香烟烟雾。我们将测试MME产生弹性蛋白的假设 片段介导单核细胞趋化性，单核细胞蛋白酶是 需要进行跨血管迁移。2)[蛋白酶调节] 确定巨噬细胞特异性表达ME的分子基础。 我们的假设是，巨噬细胞特异性表达ME是由 ME基因紧邻5'侧翼序列中的沉默元件。 3)[弹性蛋白纤维周转]测试假设，弹性蛋白周转 纤维（弹性蛋白和微纤维蛋白）对发育至关重要 肺气肿，因为复杂和潜在的无效性质， 弹性纤维修复

Pulmonary emphysema results when chronic exposure to cigarette smoke leads to 1) inflammatory cell recruitment within the terminal airspaces of the lung, followed by 2) release of elastolytic proteinases from the inflammatory cells, coupled with 3) inappropriate repair of elastic fibers and perhaps other extracellular matrix components. In the original proposal, we investigated the role of macrophage elastase (ME), a matrix metalloproteinase cloned and characterized in our laboratory, in the development of pulmonary emphysema. We found that human ME is capable of degrading many extracellular matrix proteins including elastin and that its expression is induced in macrophages of cigarette smokers and in patients with emphysema. To determine directly the contribution of macrophage elastase-deficient (MME-/-) mice by gene-targeting, and 3) subjected MME-/- mice and wild-type (MM+/+) litter-mates to chronic cigarette smoke exposure. We found that in contrast to MME+/+ mice, mice lacking MME (MME-/-) did not develop emphysema. Surprisingly, MME-/- mice also failed to recruit macrophages into their lungs in response to cigarette smoke. These finding suggest a causative role for MME in the pathogenesis of cigarette smoking related emphysema in mice and led to hypothesis addressing the three main facets of emphysema. 1) [inflammatory cells] Define the role of proteinases in monocyte recruitment in response to cigarette smoke. We will test the hypothesis that MME generated elastin fragments mediate monocyte chemotaxis, and that monocyte proteinases are required for transvascular migration. 2) [ proteinase regulation] Determine the molecular basis for macrophage-specific expression of ME. Our hypothesis is that macrophage-specific expression of ME is mediated by silencing elements in the immediate 5' flanking sequences of the ME gene. 3) [elastin fiber turnover] Test the hypothesis that turnover of elastin fibers (elastin and microfibril proteins) is critical to the development of emphysema because of the complex and potentially ineffective nature of elastic fiber repair.