Anti-oxidative effect of the tyrosine kinase inhibitor nintedanib: a potential therapy for chronic lung allograft dysfunction?
Anti-oxidative effect of the tyrosine kinase inhibitor nintedanib: a potential therapy for chronic lung allograft dysfunction?
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DOI：
10.1080/01902148.2020.1738594
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发表时间：
2020-03-13
影响因子：
1.7
通讯作者：
von Suesskind-Schwendi, Marietta
中科院分区：
文献类型：
--
作者：
Boxhammer, Elke;Lehle, Karla;von Suesskind-Schwendi, Marietta
背景：肺移植术后的长期生存常常受到慢性同种异体肺功能障碍（chronic lung allograft dysfunction， CLAD）的限制。由于多种危险因素，如免疫因素或药物相关因素，慢性同种异体肺移植功能障碍发生氧化应激增加。本研究旨在探讨受体酪氨酸激酶（RTK）抑制剂尼达尼布对免疫诱导的氧化应激和药物诱导的氧化应激的抗氧化作用。方法：采用体内实验方法研究免疫诱导的氧化应激：采用转谷氨酰胺酶-2 （TGM-2）免疫组化方法研究受体酪氨酸激酶抑制剂尼达尼布对同种异体左LTx大鼠模型的潜在抗氧化作用。体外研究药物诱导的氧化应激：采用细胞活力测定、2’7’-二氯双氢荧光素（DCFDA）和谷氨酰胺转胺酶-2免疫荧光法检测尼达尼布对环孢素A （CsA）处理的大鼠肺成纤维细胞的潜在影响。结果：体内研究：无药物相互作用的同种异体移植动物表现出严重的慢性排斥反应和TGM-2的过度表达，而尼达尼布的应用显著减少了TGM-2阳性细胞的数量。体外研究：CsA浓度范围从250 ng/ml到500 ng/ml表明氧化应激是由活性氧（ROS）的增加和TGM-2的过度表达引起的，而不会诱导细胞凋亡。浓度超过1000 ng/ml会导致细胞的明显减少。用浓度在25 - 100 nM之间的尼达尼布预孵育30 min，可减少细胞内ROS的产生和TGM-2的表达。结论：受体酪氨酸激酶抑制剂尼达尼布预处理可下调ROS和TGM-2，显示其抗氧化和免疫调节作用，可能用于治疗慢性同种异体肺移植功能障碍。
Background: The long-term survival after lung transplantation (LTx) is often limited by the development of chronic lung allograft dysfunction (CLAD). Increased oxidative stress has been found to occur in chronic lung allograft dysfunction because of several risk factors, e.g. immunological factors or drug related factors. The aim of this study was to investigate the anti-oxidative effect of the receptor tyrosine kinase (RTK) inhibitor nintedanib on immunologically induced oxidative stress and on drug induced oxidative stress. Methods: In-vivo studies were used for investigation of immunologically induced oxidative stress: Immunohistochemistry of transglutaminase-2 (TGM-2) was used to figure out a potential anti-oxidative effect of receptor tyrosine kinase inhibitor nintedanib in a rat model of allogeneic left LTx. In-vitro studies were used for investigation of drug induced oxidative stress: Cell viability assay, 2'7'-dichlorodihydrofluorescein diacetate (DCFDA) and immunofluorescence of transglutaminase-2 were disposed to examine the potential impact of nintedanib on cyclosporin A (CsA) treated lung fibroblasts of the rat. Results: In-vivo studies: Allogeneic transplanted animals without drug interaction showed severe chronic rejection and an excessive expression of TGM-2, whereas the application of nintedanib significantly decreased the number of TGM-2 positive cells. In-vitro studies: Concentrations of CsA ranging from 250 ng/ml to 500 ng/ml demonstrated oxidative stress caused by an increased production of reactive oxygen species (ROS) and an overexpression of TGM-2 without inducing apoptosis in cells. Concentrations of more than 1000 ng/ml led to a considerable decrease of cellularity. 30 min-pre-incubation with nintedanib at a concentration between 25 and 100 nM reduced generation of intracellular ROS and expression of TGM-2. Conclusion: These results demonstrate a downregulation of ROS and TGM-2 by pretreatment with the receptor tyrosine kinase inhibitor nintedanib and present its potential anti-oxidative and immunomodulatory effect in the treatment of chronic lung allograft dysfunction.