Targeted induction of lung endothelial cell apoptosis causes emphysema-like changes in the mouse.
Targeted induction of lung endothelial cell apoptosis causes emphysema-like changes in the mouse.
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DOI：
10.1074/jbc.m804595200
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发表时间：
2008-10-24
期刊：
影响因子：
--
通讯作者：
Arap W
中科院分区：
文献类型：
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作者：
Giordano RJ;Lahdenranta J;Zhen L;Chukwueke U;Petrache I;Langley RR;Fidler IJ;Pasqualini R;Tuder RM;Arap W
肺气体交换依赖于丰富的毛细血管网络，其与肺泡上皮I型和II型细胞一起形成肺泡隔，即肺中的功能单位。肺泡毛细血管内皮细胞在维持肺泡结构中至关重要，因为内皮细胞完整性的破坏是几种肺部疾病的基础。在这里，我们表明，肺毛细血管内皮细胞的靶向消融概括了吸烟引起的肺气肿，最普遍的非肿瘤性肺部疾病之一，涉及的细胞事件。基于对永生化肺内皮细胞系的噬菌体文库筛选，我们鉴定了肺内皮细胞结合肽，其优先归巢于肺血管。该肽融合到一个促凋亡基序，特异性诱导体外肺内皮细胞的程序性细胞死亡以及体内肺微循环的靶向凋亡。早在肽给药后4天，小鼠就出现了与氧化应激增强、巨噬细胞流入和神经酰胺上调相关的空气空间扩大。考虑到这些都是由香烟烟雾引起的相应的人类肺气肿的关键因素，这些数据提供了证据，肺泡内皮细胞在维持肺结构和肺气肿样变化的发病机制中内皮细胞凋亡中的中心作用。因此，我们的数据能够生成一个方便的人类肺气肿小鼠模型。最后，对永生化细胞进行组合筛选，然后进行体内靶向，建立了一个实验框架，用于发现和验证其他配体导向的药物递送系统。
Pulmonary gas exchange relies on a rich capillary network, which, together with alveolar epithelial type I and II cells, form alveolar septa, the functional units in the lung. Alveolar capillary endothelial cells are critical in maintaining alveolar structure, because disruption of endothelial cell integrity underlies several lung diseases. Here we show that targeted ablation of lung capillary endothelial cells recapitulates the cellular events involved in cigarette smoke-induced emphysema, one of the most prevalent nonneoplastic lung diseases. Based on phage library screening on an immortalized lung endothelial cell line, we identified a lung endothelial cell-binding peptide, which preferentially homes to lung blood vessels. This peptide fused to a proapoptotic motif specifically induced programmed cell death of lung endothelial cells in vitro as well as targeted apoptosis of the lung microcirculation in vivo. As early as 4 days following peptide administration, mice developed air space enlargement associated with enhanced oxidative stress, influx of macrophages, and up-regulation of ceramide. Given that these are all critical elements of the corresponding human emphysema caused by cigarette smoke, these data provide evidence for a central role for the alveolar endothelial cells in the maintenance of lung structure and of endothelial cell apoptosis in the pathogenesis of emphysema-like changes. Thus, our data enable the generation of a convenient mouse model of human emphysema. Finally, combinatorial screenings on immortalized cells followed by in vivo targeting establishes an experimental framework for discovery and validation of additional ligand-directed pharmacodelivery systems.