Pleural effusion is a frequent side-effect of dasatinib, a second-generation tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. However, the underlying mechanisms remain unknown. We hypothesised that dasatinib alters endothelial integrity, resulting in increased pulmonary vascular endothelial permeability and pleural effusion. To test this, we established the first animal model of dasatinib-related pleural effusion, by treating rats with a daily regimen of high doses of dasatinib (10 mg·kg−1·day−1 for 8 weeks). Pleural ultrasonography revealed that rats chronically treated with dasatinib developed pleural effusion after 5 weeks. Consistent with these in vivo observations, dasatinib led to a rapid and reversible increase in paracellular permeability of human pulmonary endothelial cell monolayers as reflected by increased macromolecule passage, loss of vascular endothelial cadherin and zonula occludens-1 from cell–cell junctions, and the development of actin stress fibres. These results were replicated using human umbilical vein endothelial cells and confirmed by decreased endothelial resistance. Interestingly, we demonstrated that this increased endothelial permeability is a reactive oxygen species (ROS)-dependent mechanism in vitro and in vivo using a cotreatment with an antioxidant agent, N-acetylcysteine. This study shows that dasatinib alters pulmonary endothelial permeability in a ROS-dependent manner in vitro and in vivo leading to pleural effusion. The drug dasatinib causes pleural effusion by disrupting the endothelial barrier with reactive oxygen species http://ow.ly/qOGE30gamGK

中文翻译：

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达沙替尼增加内皮通透性导致胸腔积液

胸腔积液是达沙替尼的常见副作用，达沙替尼是用于治疗慢性粒细胞白血病的第二代酪氨酸激酶抑制剂。然而，潜在的机制仍然未知。我们假设达沙替尼改变内皮完整性，导致肺血管内皮通透性增加和胸腔积液。为了测试这一点，我们建立了第一个达沙替尼相关胸腔积液的动物模型，通过每天服用高剂量达沙替尼（10 mg·kg-1·day-1，持续 8 周）治疗大鼠。胸腔超声显示，长期接受达沙替尼治疗的大鼠在 5 周后出现胸腔积液。与这些体内观察结果一致，达沙替尼导致人肺内皮细胞单层的细胞旁通透性快速且可逆地增加，这反映在大分子通过增加、血管内皮钙粘蛋白和细胞-细胞连接处的血管内皮钙粘蛋白和闭塞小带-1 的丢失以及肌动蛋白应激纤维的发展。使用人脐静脉内皮细胞复制了这些结果，并通过降低的内皮电阻来证实。有趣的是，我们在体外和体内使用抗氧化剂 N-乙酰半胱氨酸共同处理证明了这种增加的内皮通透性是活性氧 (ROS) 依赖性机制。该研究表明，达沙替尼在体外和体内以 ROS 依赖性方式改变肺内皮通透性，导致胸腔积液。