Protective Effect of Inhaled Rho-Kinase Inhibitor on Lung Ischemia- Reperfusion Injury
Protective Effect of Inhaled Rho-Kinase Inhibitor on Lung Ischemia- Reperfusion Injury
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DOI：
10.1016/j.athoracsur.2016.07.067
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发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Date, Hiroshi
中科院分区：
文献类型：
--
作者：
Ohata, Keiji;Chen-Yoshikawa, Toyofumi F.;Date, Hiroshi
背景Rho激酶是一种细胞内丝氨酸/苏氨酸激酶，是细胞骨架动力学的关键调节因子。近年来的研究表明Rho激酶参与了许多器官的缺血再灌注损伤（IRI）的发病机制，但其与肺IRI的关系尚不清楚。本研究评估了Rho激酶与肺IRI的关系，并评估了吸入Rho激酶抑制剂对肺IRI的保护作用。该研究包括离体大鼠肺灌注模型，分为三组：假手术组、Rho激酶抑制剂组和热缺血组（每组n = 6）。通过灌注停止将肺暴露于60分钟的热缺血。在缺血发作时，Rho激酶抑制剂组和热缺血组分别雾化吸入新型Rho激酶抑制剂法舒地尔和生理盐水。在缺血期后重新开始灌注，并收集90分钟的生理数据。假手术组大鼠肺持续灌注，不缺血，不给药。蛋白质印迹法检测组织标本中与Rho激酶通路相关的蛋白质表达。热缺血和随后的再灌注增强Rho激酶活性，这是抑制法舒地尔吸入。法舒地尔吸入显著减弱IRI病理生理学，包括肺血管收缩、动态顺应性、肺水肿和氧合。分子生物学分析显示Rho激酶抑制肌球蛋白磷酸酶和内皮型一氧化氮合酶的活性，提示它们是Rho激酶在肺IRI发病过程中的下游靶点。本研究表明，Rho激酶激活参与肺IRI的发病机制，吸入Rho激酶抑制剂可能会减弱这种发病机制。(Ann Thorac Surg 2017; 103：476-83）（C）2017年，胸外科医师协会
Background. Rho-kinase, an intracellular serine/threonine kinase, is a key regulator of cytoskeletal dynamics. Recent studies have demonstrated that Rho-kinase is involved in the ischemia-reperfusion injury (IRI) pathogenesis of many organs; however, its involvement with lung IRI remains unclear. This study assessed the association of Rho-kinase with lung IRI and evaluated the protective effect of inhaled Rho-kinase inhibitors in lung IRI.Methods. The study included isolated rat lung perfusion models, divided into three groups: sham, Rho-kinase inhibitor, and warm ischemia (n = 6 each). The lungs were exposed to 60 minutes of warm ischemia by perfusion cessation. At the onset of ischemia, nebulized fasudil, a novel Rho-kinase inhibitor, and saline were inhaled in the Rho-kinase inhibitor and warm ischemia groups, respectively. Perfusion was restarted after the ischemic period, and physiologic data were collected for 90 minutes. Lungs in the sham group were continuously perfused without ischemia or drug administrations. Protein expression in tissue specimens related to the Rho-kinase pathway was evaluated by Western blotting.Results. Warm ischemia and subsequent reperfusion enhanced Rho-kinase activity, and this was suppressed by fasudil inhalation. Fasudil inhalation significantly attenuated IRI pathophysiology, including pulmonary vascular contraction, dynamic compliance, lung edema, and oxygenation. Molecular analysis showed that Rho-kinase suppressed myosin phosphatase and endothelial nitric oxide synthase activities, suggesting these are downstream targets of Rho-kinase during lung IRI pathogenesis.Conclusions. The present study suggests that Rho-kinase activation is involved in lung IRI pathogenesis and that inhaled Rho-kinase inhibitors may attenuate this pathogenesis. (Ann Thorac Surg 2017; 103: 476-83) (C) 2017 by The Society of Thoracic Surgeons