Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension
Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension
复制标题
DOI：
10.1172/jci86249
复制
发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Humbert, Marc
中科院分区：
文献类型：
--
作者：
Guignabert, Christophe;Phan, Carole;Humbert, Marc
肺动脉高压(PAH)是一种由达沙替尼引起的危及生命的疾病，达沙替尼是一种双重的Src和bcr-abl酪氨酸激酶抑制剂，用于治疗慢性粒细胞白血病(CML)。今天，关于达沙替尼诱导的PAH的长期发展所涉及的机制仍然存在关键问题。在这里，我们证明了慢性达沙替尼治疗会导致人类和啮齿动物的肺内皮细胞损伤。我们发现达沙替尼治疗减轻了大鼠的缺氧性肺血管收缩反应，增加了对实验性肺高压(PH)的敏感性，但在另一种BCR-ABL酪氨酸激酶抑制剂伊马替尼治疗的大鼠中没有这些作用。此外，达沙替尼以剂量依赖的方式诱导肺内皮细胞凋亡，而伊马替尼不能。达沙替尼治疗通过增加ROS的产生而介导内皮细胞功能障碍，而ROS的产生不依赖于Src家族激酶。与这些发现一致，我们观察到接受达沙替尼治疗的CML患者与接受伊马替尼治疗的CML患者相比，血清中内皮功能障碍和血管损伤的标志物升高。综上所述，我们的研究结果表明，达沙替尼导致肺血管损伤，诱导内质网应激，以及线粒体ROS的产生，从而增加对PH发生的易感性。
Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertenslon (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.