Elastin fragments drive disease progression in a murine model of emphysema
Elastin fragments drive disease progression in a murine model of emphysema
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DOI：
10.1172/jci25617
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发表时间：
2006-03-01
影响因子：
15.9
通讯作者：
Shapiro, SD
中科院分区：
文献类型：
--
作者：
Houghton, AM;Quintero, PA;Shapiro, SD
缺乏巨噬细胞弹性蛋白酶（基质金属蛋白酶-12，或MMP-12）的小鼠先前被证明可以防止香烟烟雾诱导的肺气肿的发展和肺巨噬细胞的积累，而肺巨噬细胞的积累通常是由长期暴露于香烟烟雾诱导的。为了确定实验性肺气肿中巨噬细胞积聚的基础，我们现在表明，WT烟雾暴露动物的支气管肺泡灌洗液含有体外单核细胞趋化活性，而巨噬细胞弹性蛋白酶缺陷小鼠的灌洗液中不存在这种活性。支气管肺泡灌洗液的分级显示仅在含有趋化活性的级分中存在弹性蛋白片段。针对弹性蛋白片段的mAb消除了体外趋化活性和香烟烟雾诱导的单核细胞在体内向肺的募集。猪胰腺弹性蛋白酶用于将单核细胞募集到肺中并产生肺气肿。在该模型中，弹性蛋白片段拮抗作用消除了巨噬细胞积聚和空域扩大。
Mice lacking macrophage elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung macrophages normally induced by chronic exposure to cigarette smoke. To determine the basis for macrophage accumulation in experimental emphysema, we now show that bronchoalveolar lavage fluid from WT smoke-exposed animals contained chemotactic activity for monocytes in vitro that was absent in lavage fluid from macrophage elastase-deficient mice. Fractionation of the bronchoalveolar lavage fluid demonstrated the presence of elastin fragments only in the Fractions containing chemotactic activity. An mAb against elastin fragments eliminated both the in vitro chemotactic activity and cigarette smoke-induced monocyte recruitment to the lung in vivo. Porcine pancreatic elastase was used to recruit monocytes to the lung and to generate emphysema. Elastin fragment antagonism in this model abrogated both macrophage accumulation and airspace enlargement.