Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells
Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells
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DOI：
10.1152/ajplung.00118.2010
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发表时间：
2011-04-01
影响因子：
4.9
通讯作者：
Makita, Koshi
中科院分区：
文献类型：
--
作者：
Yamakawa, Naoko;Uchida, Tokujiro;Makita, Koshi
Yamakawa N，Uchida T，Matthay MA，Makita K。体外和原位肺泡上皮细胞糖基化终末产物受体的蛋白分解释放。Am J Physiol肺细胞分子Physiol 300：L516-L525,2011。2011年1月21日首次出版；DOI：10.1152/ajpeng.00118.2010。-尽管晚期糖基化终产物受体(RAGE)已被临床研究用作肺泡上皮细胞损伤的生物标志物，但肺上皮细胞释放可溶性RAGE的机制尚未得到很好的研究。因此，这些研究旨在确定脂多糖(LPS)攻击后可溶性RAGE释放的机制。为此，将大鼠肺泡上皮细胞培养在Transwell贴片上，并于第7天在顶侧加入内毒素(500 mU g/ml)16h。第7天，RAGE主要在表面活性蛋白D阴性细胞中表达，内毒素刺激诱导RAGE释放到培养液中。这种反应可被基质金属蛋白酶(MMPs)抑制剂部分阻断。内毒素可上调MMP3和MMP13的转录水平，而RAGE的转录水平无明显变化。基质金属蛋白酶-3和基质金属蛋白酶-13可使大鼠在体肺泡灌洗液中可溶性RAGE表达，这一反应可被基质金属蛋白酶抑制剂抑制。在人类研究中，基质金属蛋白酶-3和-13抗原水平与肺水肿液样本中RAGE水平显著相关。这些结果支持了RAGE的释放主要是由肺泡上皮细胞的蛋白水解性损伤所介导的，这种损伤是在急性炎症条件下由远端空气中的蛋白酶引起的。
Yamakawa N, Uchida T, Matthay MA, Makita K. Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 300: L516-L525, 2011. First published January 21, 2011; doi: 10.1152/ajplung.00118.2010.-Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 mu g/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.