Gon Y, Sasada T, Matsui M, Hashimoto S, Takagi Y, Iwata S, Wada H, Horie T, Yodoi J
First Department of Internal Medicine, Nihon University, Tokyo, Japan.
Life Sci. 2001 Mar 9;68(16):1877-88. doi: 10.1016/s0024-3205(01)00980-8.
Bleomycin (BLM) is an anticancer drug, administration of which leads to severe lung injury, in which the generation of intracellular reactive oxygen species (ROS) is thought to participate in that. Thioredoxin (TRX) has been found to function as a powerful antioxidant by reducing ROS, and thus protecting against ROS-mediated cytotoxicity. However, a protective role of TRX in BLM-induced lung injury has not been determined. In the present study, we therefore attempted to clarify this issue. Human TRX-transfected L929 murine fibrosarcoma cells were more resistant to BLM-induced cytotoxicity than the parental and the control transfected cells, indicating that TRX plays the protective role in BLM-induced cytotoxicity. Next, we examined TRX expression in the lung of in vivo model of BLM-induced lung injury and BLM-stimulated bronchial epithelial cells in vitro to clarify the role of TRX in BLM-induced lung injury. In the lungs of BLM-treated mice, the expression of TRX was strongly induced in bronchial epithelial cells. TRX expression was also up-regulated at both the mRNA and protein levels in cultured BEC with the treatment with BLM. However, the expression of other major antioxidants, such as Cu/Zn-SOD, Mn-SOD, catalase and glutathione peroxidase, was not affected by BLM. These observations suggest that the cellular reduction and oxidation (redox) state modified by TRX is involved in the BLM resistancy and the induction of TRX in bronchial epithelial cells might play a protective role in BLM-induced lung injury.
博来霉素（BLM）是一种抗癌药物，其给药会导致严重的肺损伤，据认为细胞内活性氧（ROS）的产生参与其中。已发现硫氧还蛋白（TRX）通过还原ROS发挥强大的抗氧化剂作用，从而防止ROS介导的细胞毒性。然而，TRX在博来霉素诱导的肺损伤中的保护作用尚未确定。因此，在本研究中，我们试图阐明这个问题。与亲本细胞和对照转染细胞相比，转染了人TRX的L929小鼠纤维肉瘤细胞对博来霉素诱导的细胞毒性更具抗性，这表明TRX在博来霉素诱导的细胞毒性中发挥保护作用。接下来，我们检测了博来霉素诱导的肺损伤体内模型的肺组织以及体外博来霉素刺激的支气管上皮细胞中TRX的表达，以阐明TRX在博来霉素诱导的肺损伤中的作用。在博来霉素处理的小鼠肺组织中，支气管上皮细胞中TRX的表达被强烈诱导。在用博来霉素处理的培养支气管上皮细胞中，TRX的表达在mRNA和蛋白质水平均上调。然而，其他主要抗氧化剂如铜/锌超氧化物歧化酶、锰超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的表达不受博来霉素影响。这些观察结果表明，由TRX修饰的细胞氧化还原状态与博来霉素抗性有关，支气管上皮细胞中TRX的诱导可能在博来霉素诱导的肺损伤中起保护作用。
