Laboratory of Radiopathology and Experimental Therapeutics, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France.
PLoS One. 2012;7(4):e35740. doi: 10.1371/journal.pone.0035740. Epub 2012 Apr 26.
Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 -/- mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 -/- compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 -/- mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 -/- mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.
正常组织毒性仍然是临床放射治疗中的一个剂量限制因素。最近，纤溶酶原激活物抑制剂 1（SERPINE1/PAI-1）被报道为晚期放射性肠损伤的重要介质。然而，PAI-1 是否在急性放射性肠损伤中起作用尚不清楚，我们假设 PAI-1 可能在血管内皮细胞的放射敏感性中起作用。在体内，在 PAI-1-/-小鼠的放射性肠炎模型中，定量分析了辐射敏感区、上皮和微血管内皮细胞的凋亡。在体外，研究了 PAI-1 在辐射诱导的内皮细胞（ECs）死亡中的作用。与 Wt 小鼠相比，照射后 PAI-1-/-小鼠的凋亡 ECs 水平较低。这与微血管密度的保持有关，因此 PAI-1-/-小鼠的黏膜完整性更好。在体外，照射迅速刺激 ECs 中 PAI-1 的表达，稳定过表达 PAI-1 的 ECs 的辐射敏感性增加，而 PAI-1 敲低则增加了照射后 EC 的存活。此外，与 WtECs 相比，PAI-1-/-小鼠来源的 ECs 对辐射诱导的细胞死亡更具抵抗力，这与 Akt 通路的激活有关。本研究表明，PAI-1 在肠内皮细胞辐射诱导的细胞死亡中起关键作用，并提示这强烈促进了放射性肠损伤的进展。
