Cadmium adaptation in the lung - a double-edged sword?
Cadmium adaptation in the lung - a double-edged sword?
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DOI：
10.1016/s0300-483x(00)00436-4
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发表时间：
2001-03-07
期刊：
影响因子：
4.5
通讯作者：
Watkin, RD
中科院分区：
文献类型：
--
作者：
Hart, BA;Potts, RJ;Watkin, RD
这篇综述文章讨论了肺适应镉(Cd)的主要细胞和分子反应，这可能最终导致Cd致癌。Cd适应的特征包括II型肺泡上皮干细胞的增殖和肥大，涉及多形核白细胞的炎症反应，以及几种耐药因子基因和蛋白表达的增加。最显著的生化变化与镉诱导的金属硫蛋白上调有关，金属硫蛋白是一种富含半胱氨酸的金属结合蛋白，可以隔离镉，并具有相当大的清除自由基的能力。谷胱甘肽水平的升高和与谷氨酰半胱氨酸合成酶(谷氨酰半胱氨酸合成酶调节和催化亚基)及其代谢(谷胱甘肽S转移酶)的合成有关的酶的诱导也是肺适应性反应的重要组成部分。最初，增强几个重要的细胞防御系统对镉暴露的反应可能是有益的。然而，最近的证据表明，CD适应性表型可能会产生有害的后果，可能是一把双刃剑。研究发现，镉适应的肺泡上皮细胞修复DNA损伤的能力降低，部分原因是两种碱基切除修复酶(8-氧鸟嘌呤-DNA糖基酶和核酸内切酶III)的抑制。由于未修复的DNA损伤而导致遗传异常的细胞通常会通过细胞凋亡从肺中移除。然而，另一项研究表明，与不适应的细胞相比，CD适应的细胞在氧化剂挑战后的凋亡细胞死亡显著减少。抑制细胞凋亡可以使肿瘤前期或肿瘤细胞存活，有利于它们的克隆性扩张，最终促进肿瘤的发展。更好的抗氧化剂防御力的存在也有望增加这些肿瘤对化疗药物的耐药性。(C)2001年爱思唯尔爱尔兰科学有限公司。版权所有。
This review article discusses the major cellular and molecular responses characterizing pulmonary adaptation to cadmium (Cd) that may ultimately contribute to Cd carcinogenesis. Hallmarks of Cd adaptation include hyperplasia and hypertrophy of type II alveolar epithelial stem cells, an inflammatory response involving polymorphonuclear leukocytes, and the increased gene and protein expression of several resistance factors. The most prominent biochemical change is associated with Cd-induced up-regulation of metallothionein, a cysteine-rich, metal-binding protein that sequesters Cd and also possesses considerable free radical scavenging ability. Increased levels of glutathione (GSH) and induction of enzymes involved with both the synthesis of GSH (gamma -glutamylcysteine synthetase regulatory and catalytic subunits) and its metabolism (GSH S-transferases) also constitute important components of the pulmonary adaptive response. Enhancement of several important cellular defense systems in response to Cd exposure may, at first, appear to be beneficial. However, recent evidence suggests that the Cd-adaptive phenotype could have deleterious consequences and may represent a double-edged sword. It has been discovered that Cd-adapted alveolar epithelial cells have a reduced ability to repair DNA damage due, in part, to the inhibition of two base excision repair enzymes (8-oxoguanine-DNA glycosylase and endonuclease III). Cells with genetic aberrations resulting from unrepaired DNA lesions would normally be removed from the lung by apoptosis. However, another study has demonstrated that apoptotic cell death, following an oxidant challenge, is significantly attenuated in Cd-adapted cells compared to non-adapted counterparts. Suppressed apoptosis could leave pre-neoplastic or neoplastic cells alive, favor their clonal expansion, and ultimately promote tumor development. The presence of superior antioxidant defenses would also be expected to increase the resistance of these tumors to chemotherapeutic agents. (C) 2001 Elsevier Science Ireland-Ltd. All rights reserved.