Attenuation of Lung Ischemia-Reperfusion Injury by Rho-Associated Kinase Inhibition in a Rat Model of Lung Transplantation
Attenuation of Lung Ischemia-Reperfusion Injury by Rho-Associated Kinase Inhibition in a Rat Model of Lung Transplantation
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DOI：
10.5761/atcs.oa.13-00095
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发表时间：
2014-01-01
影响因子：
1.3
通讯作者：
Sawafuji, Makoto
中科院分区：
文献类型：
--
作者：
Kohno, Mitsutomo;Watanabe, Masazumi;Sawafuji, Makoto
背景：小 GTP 酶 Rho 和 Rho 相关卷曲螺旋形成蛋白激酶 (ROCK) 的信号传导通路调节内皮细胞的收缩。我们研究了特异性 ROCK 抑制剂 Y-27632 的作用，以阐明 Rho/ROCK 在单肺移植 (LTX) 大鼠模型缺血再灌注肺损伤发病机制中的作用。方法：我们用 Euro-Collins 溶液冲洗 5 个供体大鼠肺，用 Euro-Collins + Y-27632, 0.03 冲洗 5 个供体肺 mg/ml，并将肺在4℃下保存6小时，然后再灌注4小时。 Y-27632 处理肺的 5 只大鼠接受者还接受了 10 mg/kg Y-27632 腹膜内推注。再灌注前30分钟。结果：用Y-27632预处理供肺和受体大鼠显着抑制LTX后水肿，而通透性指数仅略有下降。治疗后的肺泡灌洗液中（1）中性粒细胞和巨噬细胞的数量，以及（2）肿瘤坏死因子（TNF）-α的浓度显着低于未治疗的肺。结论：Y-27632（1）抑制炎症细胞迁移到肺泡腔，（2）减少TNF-α的产生，并且 (3)减轻LTX后的水肿。内皮Rho和ROCK可能在LTX后损伤的发病机制中发挥重要作用。
Background: A signaling pathway of the small GTPase Rho and Rho-associated coiled-coil-forming protein kinase (ROCK), regulates the contraction of endothelial cells. We studied the effects of Y-27632, a specific ROCK inhibitor, to clarify the role of Rho/ROCK in the pathogenesis of ischemia-reperfusion lung injury in a rat model of single-lung transplantation (LTX).Methods: We flushed 5 donor rat lungs with Euro-Collins solution, and 5 donor lungs with Euro-Collins + Y-27632, 0.03 mg/ml, and preserved the lungs for 6 h at 4 degrees C before reperfusion for 4 h. The 5 rat recipients of Y-27632-treated lungs also received a 10-mg/kg bolus of Y-27632 i.p. 30 min before reperfusion.Results: Pretreatment of the donor lungs and recipient rats with Y-27632 prominently suppressed the post-LTX edema, while the permeability index was only slightly decreased. The (1) numbers of neutrophils and macrophages, and (2) tumor necrosis factor (TNF)-alpha concentration, were significantly lower in the bronchoalveolar lavage fluid of treated than untreated lungs.Conclusions: Y-27632 (1) inhibited the migration of inflammatory cells into the alveolar space, (2) decreased the production of TNF-alpha, and (3) attenuated the edema after LTX. Endothelial Rho and ROCK may play an important role in the pathogenesis of post-LTX injury.