Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 94602, USA.
Am J Respir Cell Mol Biol. 2011 Dec;45(6):1195-202. doi: 10.1165/rcmb.2011-0170OC. Epub 2011 Jun 17.
Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed by pulmonary tissue that influence alveolar type (AT) II-ATI transition required for normal alveolar formation. However, the precise contribution of RAGE in interactions between pulmonary epithelium and splanchnic mesenchyme during lung organogenesis remains uncertain. To test the hypothesis that RAGE misexpression adversely affects lung morphogenesis, conditional transgenic mice were generated that overexpress RAGE. Mice that overexpress RAGE throughout embryogenesis experienced 100% mortality and significant lung hypoplasia coincident with large, vacuous areas in the periphery when compared with normal airway and alveolar architecture observed in control mouse lungs. Flow cytometry and immunohistochemistry employing cell-specific markers for distal (forkhead box protein A2) and respiratory (thyroid transcription factor-1) epithelium, ATII cells (pro-surfactant protein-C), and ATI cells (T1-α) demonstrated anomalies in key epithelial cell populations resulting from RAGE up-regulation. These results reveal that precise regulation of RAGE expression is required during lung formation. Furthermore, abundant RAGE results in profound alterations in epithelial cell differentiation that culminate in severe respiratory distress and perinatal lethality.
晚期糖基化终产物受体（RAGE）是肺部组织表达的细胞表面受体，它影响正常肺泡形成所必需的肺泡 II 型-肺泡 I 型转化。然而，RAGE 在肺发生过程中肺上皮和内脏间充质之间相互作用中的精确贡献仍然不确定。为了验证 RAGE 异常表达会对肺形态发生产生不利影响的假设，我们生成了条件性转基因小鼠，使其过表达 RAGE。与正常气道和肺泡结构相比，在胚胎发生过程中全身过表达 RAGE 的小鼠的死亡率为 100%，并且肺发育不全显著，同时在外周有大的空泡区。采用远端（叉头框蛋白 A2）和呼吸（甲状腺转录因子-1）上皮、ATII 细胞（前表面活性剂蛋白-C）和 ATI 细胞（T1-α）的细胞特异性标记物进行的流式细胞术和免疫组织化学分析表明，RAGE 上调导致关键上皮细胞群出现异常。这些结果表明，在肺形成过程中需要严格调控 RAGE 的表达。此外，大量的 RAGE 导致上皮细胞分化的深刻改变，最终导致严重的呼吸窘迫和围产期致死。
