Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib
Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib
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DOI：
10.1161/circulationaha.112.134304
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发表时间：
2012-12-04
期刊：
影响因子：
37.8
通讯作者：
Amerongen, Geerten P. van Nieuw
中科院分区：
文献类型：
--
作者：
Aman, Jurjan;van Bezu, Jan;Amerongen, Geerten P. van Nieuw
背景-脓毒症和急性肺损伤中观察到的组织水肿和内皮屏障功能障碍具有很高的发病率和死亡率，但目前缺乏专门的治疗方法。在最近的病例报告中，我们描述了酪氨酸激酶抑制剂伊马替尼通过一种未知的机制治疗肺水肿的快速消退。在此，我们探讨了伊马替尼对内皮屏障功能障碍和水肿形成的影响。方法和结果-我们在体外和体内评价了伊马替尼对内皮屏障功能的影响。在人类大血管和微血管内皮单分子层中，伊马替尼可减轻凝血酶和组胺诱导的内皮屏障功能障碍。对伊马替尼敏感激酶的小干扰RNA敲除表明，伊马替尼通过抑制Abl相关基因激酶(Arg/ABL2)来减轻内皮屏障功能障碍，Abl相关基因激酶是一种先前未知的内皮屏障功能障碍的介导物。事实上，Arg是通过凝血酶、组胺和血管内皮生长因子刺激内皮细胞而激活的。伊马替尼通过增强rac1活性和加强内皮细胞与细胞外基质的黏附来限制Arg介导的内皮屏障功能障碍。使用小鼠血管渗漏模型作为概念验证，我们发现伊马替尼预处理对血管内皮生长因子诱导的皮肤血管渗漏具有保护作用，并有效地防止了肺水肿的形成。在脓毒症小鼠模型中，伊马替尼治疗(脓毒症诱导后6小时和18小时)减少了肾和肺的血管渗漏(脓毒症诱导后24小时)。结论-因此，伊马替尼通过抑制精氨酸来预防内皮屏障功能障碍和水肿的形成。这些发现表明伊马替尼是一种治疗通透性水肿的有前途的方法，并表明精氨酸是治疗水肿的新靶点。(发行量。2012；126：2728-2738。)
Background-Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case report, we described fast resolution of pulmonary edema on treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation.Methods and Results-We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro- and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. Small interfering RNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-related gene kinase (Arg/Abl2), a previously unknown mediator of endothelial barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extracellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against vascular endothelial growth factor-induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis, imatinib treatment (6 hours and 18 hours after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24 hours after induction of sepsis).Conclusions-Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema and indicate Arg as novel target for edema treatment. (Circulation. 2012;126:2728-2738.)