Mining the acute respiratory distress syndrome proteome: Identification of the insulin-like growth factor (IGF)/IGF-binding protein-3 pathway in acute lung injury
Mining the acute respiratory distress syndrome proteome: Identification of the insulin-like growth factor (IGF)/IGF-binding protein-3 pathway in acute lung injury
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DOI：
10.2353/ajpath.2006.050612
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发表时间：
2006-07-01
影响因子：
6
通讯作者：
Goodlett, David R.
中科院分区：
文献类型：
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作者：
Schnapp, Lynn M.;Donohoe, Samuel;Goodlett, David R.
为了获得更完整的急性呼吸窘迫综合征（ARDS）空气环境的蛋白质谱并识别新的介质，我们使用鸟枪蛋白质组学分析了支气管肺泡灌洗液（BALF）。利用三名患者的BALF，我们共鉴定出870种不同的蛋白质，比之前的报道增加了近10倍。在鉴定的蛋白质中有已知的肺损伤标志物，如表面活性剂、蛋白酶和血清蛋白。我们还发现了一些以前未在ARDS患者中发现的生物学上有趣的蛋白质，包括胰岛素样生长因子结合蛋白-3 （IGFBP-3）。由于已知IGFBP-3在调节细胞存活中的作用，我们通过酶联免疫吸附法测定了ARDS BALF中IGFBP-3的水平。正常对照的IGFBP-3水平较低，而早期ARDS患者的IGFBP-3水平显著升高。IGF通路通过1型IGF受体作用，抑制肺成纤维细胞的凋亡，但不抑制肺上皮细胞的凋亡。此外，在ARDS半胱氨酸中，IGF的缺失导致成纤维细胞凋亡增强。我们的数据表明，IGFBP-3/IGF通路参与肺损伤的发病机制，说明了散弹枪蛋白质组学在分类复杂生物体液（如BALF）中存在的蛋白质方面的能力，由此可以提出和验证假设。
To obtain a more complete protein profile of the airspace milieu in acute respiratory distress syndrome (ARDS) and to identify new mediators, we analyzed bronchoalveolar lavage fluid (BALF) by shotgun proteomics. Using BALF from three patients, we identified a total of 870 different proteins, a nearly 10-fold increase from previous reports. Among the proteins identified were known markers of lung injury, such as surfactant, proteases, and serum proteins. We also identified several biologically interesting proteins not previously identified in patients with ARDS, including insulin-like growth factor-binding protein-3 (IGFBP-3). Because of the known role of IGFBP-3 in regulating cell survival, we measured IGFBP-3 levels by enzyme-linked imnumosorbent assay in ARDS BALF. Normal controls had low levels of IGFBP-3, whereas patients with early ARDS had a significant increase in IGFBP-3. The IGF pathway, acting through the type 1 IGF-receptor, repressed apoptosis of lung fibroblasts but not lung epithelial cells. Furthermore, depletion of IGF in ARDS BALF led to enhanced fibroblast apoptosis. Our data suggest that the IGFBP-3/IGF pathway is involved in the pathogenesis of lung injury, illustrating the power of shotgun proteomics to catalog proteins present in complex biological fluids, such as BALF, from which hypotheses can be developed and tested.