PI3K signaling is required for prostaglandin-induced mucosal recovery in ischemia-injured porcine ileum
PI3K signaling is required for prostaglandin-induced mucosal recovery in ischemia-injured porcine ileum
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DOI：
10.1152/ajpgi.00121.2002
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发表时间：
2003-01-01
影响因子：
4.5
通讯作者：
Blikslager, AT
中科院分区：
文献类型：
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作者：
Little, D;Dean, RA;Blikslager, AT
我们以前已经证明，PGE（2）和PGI（2）诱导缺血损伤的猪回肠粘膜跨上皮阻力（TER）的恢复，与Cl-分泌的初始增加有关。我们认为，后者产生的渗透梯度，刺激紧密连接重新密封。由于有证据表明磷脂酰肌醇3-激酶（PI 3 K）参与调节紧密连接组装，我们推测该信号通路参与PG诱导的粘膜恢复。使猪回肠经受45分钟的缺血，之后监测TER持续180分钟的恢复期。内源性PG的产生被吲哚美辛（5 μ M）抑制。PGE（2）（1 μ M）和PGI（2）（1 μ M）刺激TER的恢复，而渗透剂尿素（300 mosmol/kgH（2）O）的血清学应用则抑制TER的恢复。PI 3 K抑制剂渥曼青霉素（10 nM）阻断了PG或粘膜尿素引起的TER恢复。恢复上皮的免疫荧光成像显示，PG恢复occludin和封闭小带-1分布到上皮间连接，这种模式被破坏的预处理与渥曼青霉素。这些实验表明，前列腺素通过涉及跨上皮渗透梯度和紧密连接蛋白分布的PI 3 K依赖性恢复的机制刺激细胞旁阻力的恢复。
We have previously shown that PGE(2) and PGI(2) induce recovery of transepithelial resistance (TER) in ischemia-injured porcine ileal mucosa, associated with initial increases in Cl- secretion. We believe that the latter generates an osmotic gradient that stimulates resealing of tight junctions. Because of evidence implicating phosphatidylinositol 3-kinase (PI3K) in regulating tight junction assembly, we postulated that this signaling pathway is involved in PG-induced mucosal recovery. Porcine ileum was subjected to 45 min of ischemia, after which TER was monitored for a 180-min recovery period. Endogenous PG production was inhibited with indomethacin (5 muM). PGE(2) (1 muM) and PGI(2) (1 muM) stimulated recovery of TER, which was inhibited by serosal application of the osmotic agent urea (300 mosmol/kgH(2)O). The PI3K inhibitor wortmannin (10 nM) blocked recovery of TER in response to PGs or mucosal urea. Immunofluorescence imaging of recovering epithelium revealed that PGs restored occludin and zonula occludens-1 distribution to interepithelial junctions, and this pattern was disrupted by pretreatment with wortmannin. These experiments suggest that PGs stimulate recovery of paracellular resistance via a mechanism involving transepithelial osmotic gradients and PI3K-dependent restoration of tight junction protein distribution.